Androgen receptor modulator compounds and methods

ABSTRACT

Compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. In particular, preparation and methods of use of non-steroidal compounds and compositions that are agonists, partial agonists, and antagonists for the androgen receptor (AR) are described. Further, described are the methods of making and use of critical intermediates including a stereoselective synthetic route to intermediates for the AR modulators.

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/150,988, filed Aug. 27, 1999, the entire disclosure ofwhich is incorporated by reference herein.

FIELD OF THE INVENTION

[0002] This invention relates to non-steroidal compounds that aremodulators (i.e. agonists and antagonists) of androgen receptors, and tomethods for the making and use of such compounds.

BACKGROUND OF THE INVENTION

[0003] Intracellular receptors (IRs) form a class ofstructurally-related genetic regulators scientists have named “liganddependent transcription factors.” R. M. Evans, Science, 240:889 (1988).Steroid receptors are a recognized subset of the IRs, including theprogesterone receptor (PR), androgen receptor (AR), estrogen receptor(ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR).Regulation of a gene by such factors requires both the IR itself and acorresponding ligand, which has the ability to selectively bind to theIR in a way that affects gene transcription.

[0004] Ligands to the IRs can include low molecular weight nativemolecules, such as the hormones progesterone, estrogen and testosterone,as well as synthetic derivative compounds such as medroxyprogesteroneacetate, diethylstilbesterol and 19-nortestosterone. These ligands, whenpresent in the fluid surrounding a cell, pass through the outer cellmembrane by passive diffusion and bind to specific IR proteins to createa ligand/receptor complex. This complex then translocates to the cell'snucleus, where it binds to a specific gene or genes present in thecell's DNA. Once bound to DNA, the complex modulates the production ofthe protein encoded by that gene. In this regard, a compound that bindsan IR and mimics the effect of the native ligand is referred to as an“agonist”, while a compound that inhibits the effect of the nativeligand is called an “antagonist.”

[0005] Ligands to the steroid receptors are known to play an importantrole in health of both women and men. For example, the native femaleligand, progesterone, as well as synthetic analogues, such as norgestrel(18-homonorethisterone) and norethisterone(17α-ethinyl-19-nortestosterone), are used in birth controlformulations, typically in combination with the female hormone estrogenor synthetic estrogen analogues, as effective modulators of both PR andER. On the other hand, antagonists to PR are potentially useful intreating chronic disorders, such as certain hormone dependent cancers ofthe breast, ovaries, and uterus, and in treating non-malignantconditions such as uterine fibroids and endometriosis, a leading causeof infertility in women. Similarly, AR antagonists, such as cyproteroneacetate and flutamide, have proved useful in the treatment of prostatichyperplasia and cancer of the prostate.

[0006] The effectiveness of known modulators of steroid receptors isoften tempered by their undesired side-effect profile, particularlyduring long-term administration. For example, the effectiveness ofprogesterone and estrogen agonists, such as norgestrel anddiethylstilbesterol respectively, as female birth control agents must beweighed against the increased risk of breast cancer and heart disease towomen taking such agents. Similarly, the progesterone antagonist,mifepristone (RU486), if administered for chronic indications, such asuterine fibroids, endometriosis and certain hormone-dependent cancers,could lead to homeostatic imbalances in a patient due to its inherentcross-reactivity as a GR antagonist. Accordingly, identification ofcompounds that have good specificity for one or more steroid receptors,but have reduced or no cross-reactivity for other steroid orintracellular receptors, would be of significant value in the treatmentof male and female hormone responsive diseases.

[0007] A group of quinolinone and coumarin analogs having a fused ringsystem of the aryl, piperidine, pyrrolidine, or indoline series havebeen described as androgen modulators. See U.S. Pat. No. 5,696,130; Int.Patent Appl. WO 97/49709; L. G. Hamann, et. al. J. Med. Chem.,41:623-639 (1998); J. P. Edwards, et. al., Bioorg. Med. Chem. Lett.,8:745-750 (1998).

[0008] In addition, novel enantioselective synthetic routes to N-alkylor N-aryl 3,4-dihydro-2H-1,4-benzoxazine compounds are described. Suchcompounds are key intermediates in the preparation of quinolinones andother fused ring structures of the instant invention. Often, when suchfused-ring compounds are chiral and possess biological activity, onlyone enantiomer is biologically active, or the enantiomers possessdifferent biological activity. Isolating and testing such enantiomersoften yields a compound with enhanced selectivity, lower toxicity, andgreater potency. Therefore, it would be highly advantageous toselectively prepare these types of compounds in the desiredconfiguration. See Atarashi S., et al., J. Heterocyclic Chem., 28:329(1991); Xie, L. J., Chinese Chemical Letters, 6:857 (1995); Mitscher, L.A., et al., J. Med. Chem., 30:2283 (1987).

[0009] The entire disclosures of the publications and referencesreferred to above and hereafter in this specification are incorporatedherein by reference.

SUMMARY OF THE INVENTION

[0010] The present invention is directed to novel compounds,pharmaceutical compositions, and methods for modulating processesmediated by steroid receptors. More particularly, the invention relatesto non-steroidal compounds and compositions that are high-affinity,high-specificity agonists, partial agonists (i.e., partial activatorsand/or tissue-specific activators) and antagonists for the androgenreceptor (AR). Also provided are methods of making and using suchcompounds and pharmaceutical compositions, as well as criticalintermediates used in their synthesis.

[0011] In another aspect of the invention, a stereoselective syntheticroute to intermediate compounds for these AR modulators is described.This aspect of the invention relates to preparing N-alkylated aminoalcohol intermediates stereoselectively.

[0012] These and various other advantages and features of novelty thatcharacterize the invention are pointed out with particularity in theclaims annexed hereto and forming a part hereof. The following detaileddescription of the invention provides a better understanding of theinvention, its advantages, and objects obtained by its use, as well aspreferred embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0013] In accordance with the present invention, we have developed novelcompounds, compositions, and methods of preparation of non-steroidalcompounds that are AR modulators. Specifically, we have developed highaffinity, high specificity agonists, partial agonists (i.e., partialactivators and/or tissue-specific activators) and antagonists for theandrogen receptor and methods of preparing these compounds andcompositions.

[0014] In accordance with the present invention and as used herein, thefollowing structure definitions are provided for nomenclature purposes.Furthermore, in an effort to maintain consistency in the naming ofcompounds of similar structure but differing substituents, the compoundsdescribed herein are named according to the following generalguidelines. The numbering system for the location of substituents onsuch compounds is also provided.

[0015] The term “alkyl” refers to an optionally substitutedstraight-chain or branched-chain hydrocarbon radical having from 1 toabout 10 carbon atoms, more preferably from 1 to about 6 carbon atoms,and most preferably from 1 to about 4 carbon atoms. Examples of alkylradical include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, octyl and the like.

[0016] The term “alkenyl” refers to a straight-chain or branched-chainhydrocarbon radical having one or more carbon-carbon double-bonds andhaving from 2 to about 10 carbon atoms, preferably from 2 to about 6carbon atoms, and most preferably from 2 to about 4 carbon atoms.Preferred alkenyl groups include allyl. Examples of alkenyl radicalsinclude ethenyl, propenyl, 1,4-butadienyl and the like.

[0017] The term “allyl” refers to the radical CH₂═CH—CH₂.

[0018] The term “alkynyl” refers to a straight-chain or branched-chainhydrocarbon radical having one or more carbon-carbon triple-bonds andhaving from 2 to about 10 carbon atoms, preferably from 2 to about 6carbon atoms, and most preferably from 2 to about 4 carbon atoms.Examples of alkynyl radicals include ethynyl, propynyl, butynyl and thelike.

[0019] The term aryl refers to optionally substituted aromatic ringsystems. The term aryl includes monocyclic aromatic rings, polycyclicaromatic ring systems, and polyaromatic ring systems. The polyaromaticand polycyclic ring systems may contain from two to four, morepreferably two to three, and most preferably two, rings.

[0020] The term “heteroaryl” refers to optionally substituted aromaticring systems having one or more heteroatoms such as, for example,oxygen, nitrogen and sulfur. The term heteroaryl may include five- orsix-membered heterocyclic rings, polycyclic heteroaromatic ring systems,and polyheteroaromatic ring systems where the ring system has from twoto four, more preferably two to three, and most preferably two, rings.The terms heterocyclic, polycyclic heteroaromatic, andpolyheteroaromatic include ring systems containing optionallysubstituted heteroaromatic rings having more than one heteroatom asdescribed above (e.g., a six membered ring with two nitrogens),including polyheterocyclic ring systems from two to four, morepreferably two to three, and most preferably two, rings. The termheteroaryl includes ring systems such as, for example, pyridine,quinoline, furan, thiophene, pyrrole, imidazole and pyrazole.

[0021] The term “alkoxy” refers to an alkyl ether radical wherein theterm alkyl is defined as above. Examples of alkoxy radicals includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like.

[0022] The term “aryloxy” refers to an aryl ether radical wherein theterm aryl is defined as above. Examples of aryloxy radicals includephenoxy, benzyloxy and the like.

[0023] The term “cycloalkyl” refers to a saturated or partiallysaturated monocyclic, bicyclic or tricyclic alkyl radical wherein eachcyclic moiety has about 3 to about 8 carbon atoms. Examples ofcycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

[0024] The term “cycloalkylalkyl” refers to an alkyl radical as definedabove which is substituted by a cycloalkyl radical having from about 3to about 8 carbon atoms.

[0025] The term “arylalkyl” refers to an alkyl radical as defined abovein which one hydrogen atom is replaced by an aryl radical as definedabove, such as, for example, benzyl, 2-phenylethyl and the like.Preferably, arylalkyl refers to arylmethyl.

[0026] The terms alkyl, alkenyl, and alkynyl include optionallysubstituted straight-chain, branched-chain, cyclic, saturated and/orunsaturated structures, and combinations thereof.

[0027] The terms cycloalkyl, allyl, aryl, arylalkyl, heteroaryl,alkynyl, and alkenyl include optionally substituted cycloalkyl, allyl,aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups.

[0028] The terms haloalkyl, haloalkenyl and haloalkynyl include alkyl,alkenyl and alkynyl structures, as described above, that are substitutedwith one or more fluorines, chlorines, bromines or iodines, or withcombinations thereof.

[0029] The terms heteroalkyl, heteroalkenyl and heteroalkynyl includeoptionally substituted alkyl, alkenyl and alkynyl structures, asdescribed above, in which one or more skeletal atoms are oxygen,nitrogen, sulfur, or combinations thereof.

[0030] The substituents of an “optionally substituted” structureinclude, for example, one or more, preferably one to four, morepreferably one to two, of the following preferred substituents: alkyl,alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl,cycloalkylalkyl, arylalkyl, amino, alkylamino, dialkylamino, F, Cl, Br,I, CN, NO₂, NR¹⁰R¹¹, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CH₃, CF₃,C(O)CH₃, CO₂CH₃, CO₂H and C(O)NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₈cycloalkyl, C₁-C₄ heteroalkyl, and OR⁹.

[0031] A 2H-1,4-benzoxazin-3(4H)-one is represented by the followingstructure:

[0032] A 2H-1,4-benzoxazine is represented by the following structure:

[0033] A 7H-[1,4]oxazino[3,2-g]quinolin-7-one is represented by thefollowing structure:

[0034] A 1H-[1,4]oxazino[3,2-g]quinoline is represented by the followingstructure:

[0035] A 1H-[1,4]oxazino[3,2-g]quinoline-2(3H)-one is represented by thefollowing structure:

[0036] A 3H-[1,4]oxazino[3,2-g]quinolin-2,7-dione is represented by thefollowing structure:

[0037] A pyrido[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-9(8H)-one isrepresented by the following structure:

[0038] A 1H-pyrrolo[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one isrepresented by the following structure:

[0039] A quinoxalin-2(1H)-one is represented by the following structure:

[0040] A quinoxaline is represented by the following structure:

[0041] A pyrazino[3,2-g]quinolin-2,7-dione is represented by thefollowing structure:

[0042] A pyrazino[3,2-g]quinolin-7(6H)-one is represented by thefollowing structure:

[0043] Compounds of the present invention are represented by thosehaving the formulas:

[0044] wherein:

[0045] R¹ represents hydrogen, F, Cl, Br, I, NO₂, OR⁹, NR¹⁰R¹¹,S(O)_(m)R⁹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, or C₂-C₈ alkenyl,wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, alkynyl, and alkenyl groups may be optionally substituted;

[0046] R² is hydrogen, F, Cl, Br, I, CF₃, CF₂H, CFH₂, CF₂OR⁹, CH₂OR⁹,OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, or C₂-C₈ alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl,haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups maybe optionally substituted;

[0047] R³ is hydrogen, F, Cl, Br, I, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, or C₁-C₆alkyl, C₁-C₆ heteroalkyl, or C₁-C₆ haloalkyl and wherein the alkyl,heteroalkyl, and haloalkyl groups may be optionally substituted;

[0048] R⁴ and R⁵ each independently are hydrogen, OR⁹, S(O)_(m)R⁹,NR¹⁰R¹¹, C(Y)OR¹¹, C(Y)NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, or C₂-C₈ alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl,haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups maybe optionally substituted; or

[0049] R⁴ and R⁵ taken together can form a saturated or unsaturatedthree- to seven-membered ring that may be optionally substituted;

[0050] R⁶ and R⁷ each independently are hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl,heteroaryl, C₂-C₈ alkynyl, or C₂-C₈ alkenyl, wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,alkynyl, and alkenyl groups may be optionally substituted; or

[0051] R⁶ and R⁷ taken together can form a saturated or unsaturatedthree- to seven-membered ring that may be optionally substituted; or

[0052] R⁶ and R⁵ taken together can form a saturated or unsaturatedthree- to seven-membered ring that may be optionally substituted;

[0053] R⁸ is hydrogen, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl,F, Cl, Br, I, NO₂, OR⁹, NR¹⁰R¹¹ or S(O)_(m)R⁹, wherein the alkyl,heteroalkyl, and haloalkyl groups may be optionally substituted;

[0054] R⁹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, C₂-C₈ alkenyl or arylalkyl, wherein the alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groupsmay be optionally substituted;

[0055] R¹⁰ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, C₂-C₈ alkenyl, arylalkyl, SO₂R¹² or S(O)R¹², whereinthe alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl andarylalkyl groups may be optionally substituted;

[0056] R¹¹ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, C₂-C₈ alkenyl or arylalkyl, wherein the alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groupsmay be optionally substituted;

[0057] R¹² is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, C₂-C₈ alkenyl or arylalkyl, wherein the alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groupsmay be optionally substituted;

[0058] R¹³ is hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, heteroaryl, or arylalkyl, whereinthe alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl and arylalkyl groupsmay be optionally substituted; or

[0059] R¹³ and R⁴ taken together can form a saturated or unsaturatedthree- to seven-membered ring that may be optionally substituted;

[0060] R¹⁴ and R¹⁵ each independently are hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, heteroaryl,arylalkyl, C₂-C₈ alkynyl or C₂-C₈ alkenyl, wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyland alkenyl groups may be optionally substituted;

[0061] R^(A) is F, Br, Cl, I, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, OR¹⁶, NR¹⁶R¹⁷, SR¹⁶, CH₂R¹⁶, COR¹⁷, CO₂R¹⁷, CONR¹⁷R¹⁷,SOR¹⁷ or SO₂R¹⁷, wherein the alkyl, heteroalkyl, and haloalkyl groupsmay be optionally substituted;

[0062] R¹⁶ is hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl,COR¹⁷, CO₂R¹⁷ or CONR¹⁷R¹⁷, wherein the alkyl, heteroalkyl, andhaloalkyl groups may be optionally substituted;

[0063] R¹⁷ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl, wherein the alkyl, heteroalkyl, and haloalkyl groups may beoptionally substituted;

[0064] m is 0, 1 or 2;

[0065] n is 1 or 2;

[0066] V is O, S or CR¹⁴R¹⁵;

[0067] W is O, S(O)_(m), NR¹³, NC(Y)R¹¹, or NSO₂R¹¹

[0068] X and Z each independently are O, S(O)_(m), NR¹¹, NC(Y)R¹¹,NSO₂R¹² or NS(O)R¹²;

[0069] Y is O or S; and

[0070] any two of R⁴, R⁵, R⁶, R⁷, and R¹³ taken together can form asaturated or unsaturated three- to seven-membered ring that may beoptionally substituted;

[0071] and pharmaceutically acceptable salts thereof.

[0072] Preferred R¹ groups include hydrogen, F, Cl, Br, I, NO₂, OR⁹,NR¹⁰R¹¹, S(O)_(m)R⁹, C₁-C₈ alkyl, C₁-C₈ cycloalkyl, C₁-C₈ heteroalkyl,C₁-C₈ haloalkyl, allyl, C₁-C₈ aryl, C₁-C₈ arylalkyl, C₁-C₈ heteroaryl,C₂-C₈ alkynyl, and C₂-C₈ alkenyl. The alkyl, cycloalkyl, heteroalkyl,haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenylgroups may be optionally substituted. More preferred R¹ groups includeH, F, Cl, OR⁹, NR¹⁰R¹¹, S(O)_(m)R⁹, and C₁-C₂ alkyl. Particularlypreferred R¹ groups include H, F, and Cl.

[0073] Preferred R² groups include hydrogen, F, Cl, Br, I, CF₃, CF₂Cl,CF₂H, CFH₂, CF₂OR⁹, CH₂OR⁹, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈, heteroalkyl, C₁-C₈ haloalkyl, allyl, aryl, arylalkyl,heteroaryl, C₂-C₈ alkynyl, or C₂-C₈ alkenyl. The alkyl, cycloalkyl,heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups may be optionally substituted. More preferred R² groupsinclude H, F, Cl, methyl, ethyl, CF₃, CF₂H, CF₂Cl, CFH₂, and OR⁹.Particularly preferred R² groups include H, Cl, methyl, ethyl, CF₃,CF₂H, CF₂Cl.

[0074] Preferred R³ groups include hydrogen, F, Cl, Br, I, OR⁹, S(O)mR⁹,NR¹⁰R¹¹, C₁-C₆ alkyl, C₁-C₆ heteroalkyl and C₁-C₆ haloalkyl. The alkyl,heteroalkyl, and haloalkyl groups may be optionally substituted. Morepreferred R³ groups include hydrogen, F, Cl, OR⁹, NR¹⁰R¹¹, andS(O)_(m)R⁹.

[0075] Preferred R⁴ groups include H, OR⁹, C(Y)OR¹¹, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl, C₂-C₈alkenyl, aryl, arylalkyl, and heteroaryl. The alkyl, cycloalkyl,heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroarylgroups may be optionally substituted. More preferred R⁴ groups includeH, OR⁹, C(Y)OR¹¹, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, C₂-C₄alkynyl, and C₂-C₄ alkenyl. Particularly preferred R⁴ groups include H,OR⁹, C(Y)OR¹¹, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and where R⁴ and R¹³together form a five- or six-membered ring.

[0076] Also preferred are compounds where R⁴ and R¹³ together form asaturated or unsaturated three- to seven-membered ring optionallysubstituted with 1-2 substituents. Examples of such substituentsinclude, for example, hydrogen, F, Cl, Br, C₁-C₄ alkyl, C₃-C₈cycloalkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, OR⁹ and NR¹⁰R¹¹. Thealkyl, cycloalkyl, heteroalkyl, haloalkyl groups may be optionallysubstituted.

[0077] Also preferred are compounds where R⁴ and R¹³ together form afive- to seven-membered ring optionally substituted with 1-2substituents. Examples of such substituents include F, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, and OR⁹. The alkyl, heteroalkyl, andhaloalkyl groups may be optionally substituted.

[0078] Preferred R⁵ groups include H, OR⁹, C(Y)OR¹¹, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl, C₂-C₈alkenyl, aryl, arylalkyl, and heteroaryl. The alkyl, cycloalkyl,heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroarylgroups may be optionally substituted. More preferred R⁵ groups includehydrogen, OR⁹, C(Y)OR¹¹, C₁-C₄ alkyl, and C₁-C₄ haloalkyl.

[0079] Also preferred are compounds where R⁴ and R⁵ taken together forma saturated or unsaturated three- to seven-membered ring that may beoptionally substituted.

[0080] Preferred R⁶ groups include hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, allyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl,C₂-C₈ alkenyl, aryl, arylalkyl and heteroaryl. The alkyl, cycloalkyl,allyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl andheteroaryl groups may be optionally substituted. More preferred R⁶groups include hydrogen, CH₃, and CH₂CH₃.

[0081] Also preferred are compounds where R⁶ and R⁵ taken together forma saturated or unsaturated three- to seven-membered ring that may beoptionally substituted.

[0082] Preferred R⁷ groups include hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl, C₂-C₈alkenyl, aryl, arylalkyl and heteroaryl. The alkyl, cycloalkyl,heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroarylgroups may be optionally substituted. More preferred R⁷ groups includehydrogen, CH₃, and CH₂CH₃

[0083] Also preferred are compounds where R⁶ and R⁷ taken together forma saturated or unsaturated three- to seven-membered ring that may beoptionally substituted.

[0084] Preferred R⁸ groups include hydrogen, F, Cl, Br, I, NO₂, OR⁹,S(O)_(m)R⁹, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, andNR¹⁰R¹¹. The alkyl, heteroalkyl and haloalkyl groups may be optionallysubstituted. More preferred R⁸ groups include hydrogen and F.

[0085] Preferred R⁹ groups include hydrogen, C(Y)R¹², C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, arylalkyl, C₂-C₈ alkynyland C₂-C₈ alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl,arylalkyl, alkynyl, and alkenyl groups may be optionally substituted.More preferred R⁹ groups include hydrogen, C(Y)R¹², and C₁-C₆ alkyl.Particularly preferred R⁹ groups include CH₃, CH₂CH₃, CH₂CH₂CH₃, andC(O)CH₃.

[0086] Preferred R¹⁰ groups include hydrogen, C(Y)R¹², C(Y)OR¹², SO₂R¹²,S(O)R¹², C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl,heteroaryl, arylalkyl, C₂-C₈ alkynyl, and C₂-C₈ alkenyl. The alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl, andalkenyl groups may be optionally substituted. More preferred R¹⁰ groupsinclude hydrogen, C₁-C₆ alkyl, C(Y)R¹², C(Y)OR¹², SO₂R¹².

[0087] Preferred R¹¹ groups include hydrogen, C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, arylalkyl, C₂-C₈alkynyl, and C₂-C₈ alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl,heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionallysubstituted. More preferred R¹¹ groups include hydrogen and C₁-C₄ alkyl.

[0088] Preferred R¹² groups include hydrogen, C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, allyl, arylalkyl, C₂-C₈alkynyl, C₂-C₈ alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl,heteroaryl, allyl, arylalkyl, alkynyl, and alkenyl groups may beoptionally substituted. More preferred R¹² groups include hydrogen andC₁-C₄ alkyl.

[0089] Preferred R¹³ groups include hydrogen, C₁-C₈ alkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, C₃-C₈ cycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, C₂-C₈ alkynyl, and C₂-C₈ alkenyl. The alkyl,heteroalkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkynyl, and alkenyl groups may be optionallysubstituted. More preferred R¹³ groups include C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ heteroalkyl and C₁-C₄ haloalkyl.Particularly preferred R¹³ groups include CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH₂(CH₃), CH₂(cyclopropyl), CH₂CClF₂, CH₂CHF₂, and CH₂CF₃.

[0090] Preferred R¹⁴ groups include hydrogen, C₁-C₈ alkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl, C₂-C₈ alkenyl, aryl,arylalkyl, and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl,heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionallysubstituted. More preferred R¹⁴ groups include hydrogen and C₁-C₄ alkyl.

[0091] Preferred R¹⁵ groups include hydrogen, C₁-C₈ alkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl, C₂-C₈ alkenyl, aryl,arylalkyl, and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl,heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionallysubstituted. More preferred R¹⁵ groups include hydrogen and C₁-C₄ alkyl.

[0092] Preferred R¹⁶ groups include hydrogen, C₁-C₈ alkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkynyl, C₂-C₈ alkenyl, COR¹⁷,CO₂R¹⁷, CONR¹⁷R¹⁷, aryl, and heteroaryl. The alkyl, heteroalkyl,haloalkyl, aryl, heteroaryl, alkynyl, and alkenyl groups may beoptionally substituted. More preferred R¹⁶ groups include hydrogen andC₁-C₄ alkyl.

[0093] Preferred R^(A) groups include hydrogen, F, Cl, Br, I, CN, C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, OR¹⁶, NR¹⁶R¹⁷, SR¹⁶, CH₂R¹⁶,COR¹⁷, CO₂R¹⁷, CONR¹⁷R¹⁷, SOR¹⁷, and SO₂R¹⁷. The alkyl, heteroalkyl, andhaloalkyl groups may be optionally substituted. More preferred R^(A)groups include hydrogen, F, Cl, CN, and OR¹⁶.

[0094] Preferably n is 1 or 2. More preferably, n is 1.

[0095] Preferably, m is 1 or 2. More preferably, m is 1.

[0096] Preferred V groups include O and S. More preferably, V is O.

[0097] Preferred W groups include O, S(O)_(m), NR¹³, NC(Y)R¹¹, andNSO₂R¹¹. More preferred W groups include NR¹³, NC(Y)R¹¹, and NSO₂R¹¹.Particularly preferred W groups include NR¹³.

[0098] Preferred X groups include O, S(O)_(m), NR¹¹, NC(Y)R¹¹, NSO₂R¹²and NS(O)R¹². More preferred X groups include O, S(O)_(m), and NR¹¹.Particularly preferred X groups include O and S(O)_(m). Most preferably,X is O.

[0099] Preferably Y is O.

[0100] Preferred Z groups include O, S(O)_(m), NR¹¹, NC(Y)R¹¹, NSO₂R¹²and NS(O)R¹². More preferred Z groups include O, S(O)_(m), and NR¹¹.Most preferably, Z is NH.

[0101] In one aspect, compounds of formula I are preferred.

[0102] In another aspect, compounds of formula II are preferred.

[0103] In still another aspect, compounds of formula III are preferred.

[0104] In yet another aspect, compounds of formula IV are preferred.

[0105] In one preferred aspect, R³ and R⁸ are each hydrogen; X and Y areeach independently O or S; W is NR¹³; and Z is NR¹¹.

[0106] In another preferred aspect, R³ and R⁸ are each hydrogen; X and Yare each O, W is NR¹³; and Z is NR¹¹.

[0107] In still another preferred aspect, R³ and R⁸ are each hydrogen;R² is CF₃, X and Y are each O, W is NR¹³; and Z is NR¹¹.

[0108] In yet another preferred aspect, R¹ R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹and R^(A) are each hydrogen, R² is CF₃, R¹³ is C₁-C₈ alkyl, W is NR¹³, Zis NR¹¹, X and Y are each O; and m is 1 or 2.

[0109] In yet another preferred aspect, R¹ R³, R⁶, R⁷, R⁸, R¹¹ and R^(A)are each hydrogen, R² is CF₃, R⁴, R⁵ and R¹³ are each C₁-C₈ alkyl, W isNR¹³, Z is NR¹¹, X and Y are each O; and m is 1 or 2.

[0110] In yet another preferred aspect, R¹ R³, R⁴, R⁵, R⁸, R¹¹ and R^(A)are each hydrogen, R² is CF₃, R⁶, R⁷ and R¹³ are each C₁-C₈ alkyl, W isNR¹³, Z is NR¹¹, X and Y are each O; and m is 1 or 2.

[0111] In a preferred aspect, the present invention provides apharmaceutical compositions comprising an effective amount of anandrogen receptor modulating compound of formulas I through VI shownabove wherein R¹ through R¹⁷, R^(A), V, W, X, Y, Z, m and n all have thesame definitions as given above.

[0112] In a further preferred aspect, the present invention comprisesmethods of modulating processes mediated by androgen receptorscomprising administering to a patient an effective amount of a compoundof the formulas I through VI shown above, wherein R¹ through R¹⁷, R^(A),V, W, X, Y, Z, m and n all have the same definitions as those givenabove.

[0113] Any of the compounds of the present invention can be synthesizedas pharmaceutically acceptable salts for incorporation into variouspharmaceutical compositions. As used herein, pharmaceutically acceptablesalts include, for example, hydrochloric, hydrobromic, hydroiodic,hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic,succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic,pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic,urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic,methylamino, methanesulfonic, picric, tartaric, triethylamino,dimethylamino, and tris(hydroxymethyl)aminomethane. Additionalpharmaceutically acceptable salts are known to those skilled in the art.

[0114] AR agonist, partial agonist and antagonist compounds (includingcompounds with tissue-selective AR modulator activity) of the presentinvention will prove useful in the treatment of acne (antagonist),male-pattern baldness (antagonist), male hormone replacement therapy(agonist), wasting diseases (agonist), hirsutism (antagonist),stimulation of hematopoiesis (agonist), hypogonadism (agonist),prostatic hyperplasia (antagonist), osteoporosis (agonist) malecontraception (agonist), impotence (agonist), sexual dysfunction(agonist), cancer cachexia (agonist), various hormone-dependent cancers,including, without limitation, prostate (antagonist) and breast cancerand as anabolic agents (agonist). It is understood by those of skill inthe art that a partial agonist may be used where agonist activity isdesired, or where antagonist activity is desired, depending upon the ARmodulator profile of the particular partial agonist.

[0115] It is understood by those skilled in the art that while thecompounds of the present invention will typically be employed as aselective agonists, partial agonists or antagonists, that there may beinstances where a compound with a mixed steroid receptor profile ispreferred. For example, use of a PR agonist (i.e., progestin) in femalecontraception often leads to the undesired effects of increased waterretention and acne flare-ups. In this instance, a compound that isprimarily a PR agonist, but also displays some AR and MR modulatingactivity, may prove useful. Specifically, the mixed MR effects would beuseful to control water balance in the body, while the AR effects wouldhelp to control any acne flare-ups that occur.

[0116] Furthermore, is understood by those skilled in the art that thecompounds of the present invention, including pharmaceuticalcompositions and formulations containing these compounds, can be used ina wide variety of combination therapies to treat the conditions anddiseases described above. Thus, the compounds of the present inventioncan be used in combination with other hormones and other therapies,including, without limitation, chemotherapeutic agents such ascytostatic and cytotoxic agents, immunological modifiers such asinterferons, interleukins, growth hormones and other cytokines, hormonetherapies, surgery and radiation therapy.

[0117] Representative AR modulator compounds (i.e., agonists andantagonists) according to the present invention include:

[0118] Compounds of the present invention, comprising classes ofheterocyclic nitrogen compounds and their derivatives, can be obtainedby routine chemical synthesis by those skilled in the art, e.g., bymodification of the heterocyclic nitrogen compounds disclosed or by atotal synthesis approach.

[0119] The sequences of steps for several general schemes to synthesizethe compounds of the present invention are shown below. In each of theschemes the R groups (e.g., R¹, R², etc.) correspond to the specificsubstitution patterns noted in the Examples. However, it will beunderstood by those skilled in the art that other functionalitiesdisclosed herein at the indicated positions of compounds of formulas Ithrough VI also comprise potential substituents for the analogouspositions on the structures within the schemes.

[0120] The synthesis of 7H-[1,4]oxazino[3,2-g]quinolin-7-one compounds(e.g., Structures 6 and 7), is depicted in Scheme I. The process ofScheme I begins with a cyclization of a haloacetyl halide onto2-amino-5-nitrophenol (Structure 1) with, for example, chloroacetylchloride to afford a lactam (Structure 2). See D. R. Shridhar, et al.,Org. Prep. Proc. Int., 14:195 (1982). The amide is then reduced to thecorresponding amine (Structure 3), with, for example, borane dimethylsulfide. See Y. Matsumoto, et. al., Chem. Pharm. Bull., 44:103-114(1996). Treatment of a compound such as Structure 3 with an aldehyde orits corresponding hydrate or hemiacetal, for exampletrifluoroacetaldehyde hydrate in the presence of a reducing agent, forexample, sodium cyanoborohydride, in a carboxylic acid, for exampletrifluoroacetic acid, affords a compound such as Structure 4. The nitroderivative is reduced to the corresponding aniline, with a reducingagent, for example, zinc and calcium chloride, to afford Structure 5.Treatment of the aniline with a β-ketoester or corresponding hydrate,for example 4,4,4-trifluoroacetoacetate, at elevated temperatures,followed by treatment with an acid, for example, sulfuric acid, affordsa major product (Structure 6). The cyclization of anilines as describedabove is known as a Knorr cyclization. See G. Jones, ComprehensiveHeterocyclic Chemistry, Katritzky, A. R.; Rees, C. W., eds. Pergamon,N.Y., 1984. Vol. 2, chap. 2.08, pp 421-426, the disclosure of which isherein incorporated by reference. In turn, the quinolinone nitrogen maybe alkylated by, for example, treatment with sodium hydride followed byiodomethane, to afford a compound of Structure 7. Alternatively, aquinolinone compound of Structure 6 can be converted to thecorresponding quinoline by treatment with a dehydrating agent, forexample, oxyphosphoryl chloride, to afford a compound of Structure 7A.

[0121] Alternatively, a quinolinone compound of Structure 6 can betransformed to the corresponding thio-compound by treatment with, forexample, Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] togive a 7H-[1,4]oxazino[3,2-g]quinolin-thione (e.g., Structure 8). See J.Voss, Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A.,Ed. John Wiley and Sons, New York, 1995; Vol. 1, pp 530-533, thedisclosure of which is herein incorporated by reference. Alternatively,a compound of Structure 6 (or chiral synthetic precursors of Structure6) can be separated into its corresponding enantiomers, (+)-6 and (−)-6by chiral HPLC, with, for example, a preparative Chiralpak AD columneluted with hexanes:isopropanol.

[0122] An alternate synthesis of 7H-[1,4]oxazino[3,2-g]quinolin-7-onecompounds (e.g., Structures 10 and 11) is shown in Scheme II. Theprocess of Scheme II begins with a Knorr cyclization of7-amino-3,4-dihydro-4-p-methoxybenzyl-2H-1,4-benzoxazine, and aβ-ketoester promoted by an acid, for example, sulfuric acid to afford acompound of Structure 10. Alkylation of the quinolinone nitrogen may beachieved by treatment with an aldehyde or its corresponding hydrate, forexample cyclopropanecarboxaldehyde in the presence of a reducing agent,for example, sodium cyanoborohydride, to afford the alkylated derivativeof the corresponding quinolinone compound (e.g., Structure 11).

[0123] An additional synthetic route into quinoline compounds (e.g.,Structures 16 and 18) is shown in Scheme III. The process of Scheme IIIbegins with reductive amination of 2-methoxy-4-nitroaniline with analdehyde or its corresponding hydrate, for example trifluoroacetaldehydehydrate in the presence of a reducing agent, for example, sodiumcyanoborohydride, in an acid, for example trifluoroacetic acid, toafford the corresponding N-alkylated amine. The nitro derivative isreduced to the corresponding aniline, with a reducing agent, forexample, zinc and calcium chloride, to afford a compound of Structure13. Knorr cyclization of the aniline by heating with a β-ketoester orcorresponding hydrate, for example 4,4,4-trifluoroacetoacetate, followedby treatment with an acid, for example, sulfuric acid, affords a productof Structure 14. Protection of the pyridone ring, with, for exampleisopropyl iodide mediated by a base, for example, cesium fluoride,affords the corresponding imino ether. See T. Sato, et al, Synlett 1995,845-846. Demethylation of the anisole is accomplished by treatment with,for example, sodium thiophenolate to afford a compound of Structure 15.See C. Hansson, et al., Synthesis 1975, 191. Treatment of aminophenolderivative 15 with an α-bromoester, for example, ethyl bromoacetate, anda base, with for example, potassium carbonate, affords a quinolinonecompound (Structure 16). Treatment of quinolinone compounds such asStructure 16 with an alkylidenation reagent, for example, Tebbe'sreagent, followed by reduction with, for example, sodiumcyanoborohydride, in an acid, for example acetic acid, affords aquinoline compound (e.g., Structure 17). See S. H. Pine, et. al., J.Org. Chem. 1985, 50, 1212, for the methylenation of amides. Deprotectioncan be accomplished in one of two ways. Treatment of the iminoether(Structure 17) with a mineral acid, for example hydrochloric acid,affords a 7H-[1,4]oxazino[3,2-g]quinolin-7-one compound (Structure 18).Alternatively, this transformation can be carried out with a Lewis acid,for example boron trichloride, to afford Structure 18. See T. Sala, etal., J. Chem. Soc., Perkin Trans. I, 1979, 2593. Quinolinone compoundsof Structure 18 (or any chiral synthetic precursor of 18) can beseparated into their corresponding enantiomers, (+)-18 and (−)-18 bychiral HPLC, with, for example, a preparative Chiralpak AD column elutedwith hexanes:isopropanol.

[0124] The process of converting quinolinone compounds (e.g., Structure16) into corresponding hydroxyalkyl quinoline compounds (e.g., Structure19) and then further converting into corresponding hydroxyalkyl,acyloxyalkyl, and alkyloxyalkyl quinolinone derivatives (e.g.,Structures 20, 21, and 23 respectively) is shown in Scheme IV. Theprocess of Scheme IV begins with a Tebbe olefination of a quinolinonecompound (e.g., Structure 16) followed by hydroboration of the resultantenamine to afford a hydroxyalkyl quinoline compound (Structure 19). SeeC. T. Goralski, et. al. Tetrahedron Lett. 1994, 35, 3251, for thehydroboration of enamines. Hydrolysis of the imino ether with an acid,for example hydrochloric acid, affords a hydroxy quinolinone compound(e.g., Structure 20).

[0125] Alternatively, hydrolysis of the imino ether of a hydroxyalkylquinoline compound (e.g., Structure 19) can be carried out with an acid,for example hydrochloric acid, in acetic acid, to afford an acyloxyalkylquinolinone compound (Structure 21) Alternatively, a hydroxy quinolinecompound (e.g., Structure 19) can be O-alkylated by treatment with abase, for example, sodium hydride, and an alkylating agent, with, forexample methyl iodide, to afford an alkoxyalkyl quinoline compound(e.g., Structure 22). Imino ether hydrolysis of Structure 22 with anacid, for example hydrochloric acid in acetic acid, affords analkoxyalkyl quinoline compound (Structure 23). Compound such asStructures 20, 21, or 23 can be separated into their correspondingenantiomers, (+)-20 and (−)-20, (+)-21 and (−)-21, or (+)-23 and (−)-23by chiral HPLC, with, for example, a preparative Chiralpak AD columneluted with hexanes:isopropanol.

[0126] Quinolinone compounds (e.g., Structure 16) may be converted intocorresponding quinoline-diones (e.g., Structure 24), hydroxyquinolinones (e.g., Structure 25), and quinoline-thiones (e.g.,Structures 26 and 27) by the processes shown in Scheme V. The process ofScheme V begins with the deprotection of the imino ether of Structure 16by treatment with a mineral acid, for example, hydrochloric acid, toafford a quinoline-dione compound of Structure 24. Alternatively, thistransformation can be carried out with a Lewis acid, for example, borontrichloride, to afford a quinoline-dione compound (e.g., Structure 24).See T. Sala, et al., supra. A quinoline-dione compound (e.g., Structure24) can be converted to a hydroxy quinoline compound (e.g., Structure25) by addition of an organometallic reagent, for example, methyllithium, which affords a hydroxy quinoline compound (Structure 25).

[0127] Quinoline compounds (e.g., Structure 16) can optionally beconverted into corresponding thio-compounds (e.g., Structure 25) bytreatment with, for example, Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide].Hydrolysis of the imino ether with a Lewis acid, for example, borontrichloride, affords a quinoline-thione compound (Structure 26).

[0128] A synthesis of quinolinone compounds such as Structure 30 isshown in Scheme VI. The process of Scheme VI begins with theO-alkylation of an o-aminophenol, for example, a6-amino-7-hydroxyquinoline, with a haloketone, for example,chloroacetone, mediated by a base, for example, potassium carbonate,followed by treatment with a reducing agent, for example, sodiumcyanoborohydride, in an acid, for example, acetic acid, to afford aquinoline compound of Structure 29. Hydrolysis of the imino ether ofStructure 29 with an acid, for example, hydrochloric acid in aceticacid, affords a quinolinone compound of Structure 30. Alkylation of thequinolinone nitrogen is achieved by treatment of quinolinone compounds(e.g., Structure 30) with an aldehyde or its corresponding hydrate, forexample, cyclopropanecarboxaldehyde, with a reducing agent, for example,sodium cyanoborohydride, in an acid, for example, acetic acid, affords acompound of Structure 31.

[0129] An additional route to quinolinone compounds such as Structure31D is shown in Scheme VIA. The process of Scheme VIA begins with thealkylation of a 6-aminoquinolinone with, for example,6-amino-7-methoxy-4-trifluoromethyl-1H-quinolin-2-one, with an alkylhalide, for example, isopropyl iodide, mediated by a base, for example,cesium fluoride, to afford a compound of structure 31B. Demethylation ofthe methyl ether is accomplished by treatment with, for example, sodiumthiophenolate to afford a compound of Structure 31C. Annulation of theoxazine ring can be accomplished by treatment with a vicinal dihalide,for example, 1,2-dibromoethane, mediated by a base, for examplepotassium carbonate, to afford the corresponding 1,4-oxazine, which inturn is converted to a compound of Structure 31D by treatment with anacid, for example, hydrochloric acid in acetic acid at elevatedtemperatures.

[0130] Quinolinones (e.g., Structure 35) are prepared from benzoxazines(e.g., Structure 34) by the synthetic route outlined in Scheme VII.Scheme VII begins with an alkylation of a haloketone onto2-amino-5-nitrophenol (Structure 1) with, for example, 2-bromobutanone,mediated by a base, for example, potassium carbonate, followed bytreatment with a reducing agent, for example, sodium cyanoborohydride,in an acid, for example acetic acid, to afford a benzoxazine compound(e.g., Structure 32). The benzoxazine is alkylated at the benzoxazinenitrogen by treatment of a benzoxazine compound (e.g., Structure 32)with an aldehyde, its corresponding hydrate or hemiacetal, with forexample, trifluoroacetaldehyde hydrate in the presence of a reducingagent, for example, sodium cyanoborohydride, in an acid, for exampletrifluoroacetic acid. This procedure affords an alkylated benzoxazinecompound (e.g., Structure 33). The nitro derivative of the alkylatedbenzoxazine compound (Structure 33) is reduced to the correspondinganiline by catalytic hydrogenation or with a reducing agent, forexample, zinc and calcium chloride, to afford benzoxazine compound(e.g., Structure 34). Knorr cyclization of an aminobenzoxazine (e.g.,Structure 34) by heating with a β-ketoester or corresponding hydrate,with for example, 4,4,4-trifluoroacetoacetate, followed by treatmentwith an acid, for example, sulfuric acid, affords a quinolinone product(e.g., Structure 35).

[0131] Compounds such as the 3,4-dihydro-7-nitro-2H-1,4-benzoxazines ofStructure 33 are key intermediates in the preparation of quinolinonesand other fused ring structures. In accordance with the currentinvention, we have developed a method to prepare these3,4-dihydro-7-nitro-2H-1,4-benzoxazines in enantiomerically pure form(Structure 39) from optically pure β-aminoalcohols. A synthetic methodfor the preparation of enantiomerically pure, fused ring compounds, suchas quinolinones 41, that relies upon such intermediates is shown inScheme VIII.

[0132] The asymmetric synthesis of Scheme VIII begins with the chemo-and regioselective N-alkylation of a β-aminoalcohol, either as a singleenantiomer (R or S) or its racemate, for example,(R)-2-amino-1-propanol, onto a 3,4-dihalonitrobenzene, for example,3,4-difluoronitrobenzene, mediated by a base, for example, sodiumbicarbonate, affords an optically pure arylamino alcohol (e.g.,Structure 36). Treatment of amino alcohol compounds such as Structure 36with an aldehyde or the corresponding hydrate or hemiacetal, forexample, trifluoroacetaldehyde ethyl hemiacetal, in the presence of anacid catalyst, for example p-toluenesulfonic acid, affords an opticallypure oxazolidine compound (e.g., Structure 37). Treatment of anoxazolidine compound such as Structure 37 with a reducing agent, forexample, triethylsilane, in the presence of an acid, for example, borontrifluoride etherate, affords an N-alkyl substituted amino alcoholcompound (e.g., Structure 38). Benzoxazine compounds (e.g., Structure39), may then be formed by cyclization of the N-alkyl substituted aminoalcohol compounds (e.g., Structure 38) by treatment with a base such assodium hydride. Reduction of nitro benzoxazine compounds (e.g.,Structure 39) with a reducing agent, for example, zinc and calciumchloride affords an amino benzoxazine compound (e.g., Structure 40).Treatment of an amino benzoxazine with a β-ketoester or itscorresponding hydrate, for example ethyl 4,4,4-trifluoroacetoacetate, atelevated temperatures, affords the corresponding acetanilide. Treatmentof the acetanilide with an acid, for example, sulfuric acid, affords anoptically pure quinolinone compound (e.g., Structure 41). An enantiomerof Structure 41, or a racemic mixture may be obtained by the syntheticroute as described in Scheme VIII, by starting with the enantiomer ofthe β-aminoalcohol as shown (e.g., an (S)-β-amino alcohol), or a racemicmixture of the β-aminoalcohol shown (e.g., a (+)-β-amino alcohol.Accordingly, an (S)-β-amino alcohol, employed in Scheme VII, produces an(S)-quinolinone, an (R)-β-amino alcohol, employed in Scheme VII,produces an (R)-quinolinone, and a racemic mixture of the β-aminoalcohol, employed in Scheme VII, produces a racemic mixture of thecorresponding quinolinone.

[0133] Introduction of an N-alkyl or N-methylaryl group through thereductive cleavage of oxazolidine 37, as outlined in Scheme VIII, isgenerally applicable to the preparation of enantiomerically purearylamino alcohol compounds such as Structure 38. Furthermore, theintroduction of an N-(2-haloethyl) group through the reductive cleavageof an aryl oxazolidine is a novel process that has general utility inorganic synthesis.

Preparation of N-Alkyl or N-Methylaryl Arylamino Alcohols

[0134]

[0135] In the above process sequence, R⁴⁻⁷ may optionally representhydrogen or alkyl or aryl groups, including C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl,heteroaryl, C₂-C₈ alkynyl, or C₂-C₈ alkenyl and wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,alkynyl, and alkenyl are optionally substituted with halogen, C₁-C₄alkyl, or C₁-C₄ haloalkyl;

[0136] R^(X) may represent C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, allyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, or C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl are optionally substituted with halogen, C₁-C₄ alkyl, or C₁-C₄haloalkyl.

[0137] Ar represents optionally substituted aryl or heteroaryl groups,including mono- and polycyclic structures, optionally substituted at oneor more positions.

[0138] Additional substitutions are also possible and can be readilydetermined by one skilled in the art.

[0139] The above process sequence begins with an arylamino alcohol whichis then converted into an oxazolidine with an aldehyde or thecorresponding hydrate or hemiacetal in the presence of an acid catalyst.The oxazolidine is then converted to an N-alkylarylamino alcohol byaddition of a reducing agent such as triethylsilane or sodiumcyanoborohydride in the presence of a Lewis acid such as borontrifluoride etherate or a protic acid such as trifluoroacetic acid as acatalyst. Additional aldehydes and their corresponding hydrates as wellas reducing agents may be used and are readily determined by thoseskilled in the art.

[0140] Scheme IX describes an alternative to the route of Scheme VIIIfor formation of enantiomerically pure benzoxazine compounds such asStructure 39. The route of Scheme IX offers direct access to compoundsof Structure 39 in which R⁴ and R¹³ taken together form a ringstructure. The process of Scheme IX begins with reaction of a secondaryaminoalcohol, either a single enantiomer (R or S) or its racemate, forexample 2-piperidinemethanol, with a 3,4-dihalonitrobenzene, forexample, 3,4-difluoronitrobenzene, to afford an N-aryl substitutedtertiary aminoalcohol compound such as Structure 42. Cyclization ofStructure 42, mediated by treatment with a base, for example, sodiumhydride, affords a benzoxazine compound (e.g., Structure 39).Benzoxazine compounds such as Structure 39 may then further be employedin the synthesis of quinolinone compounds as described herein.

[0141] Pyrazino-quinolinone compounds (e.g., Structure 49) may beprepared by the process described in Scheme X. The process of Scheme Xbegins with the alkylation of a 1,2-phenylenediamine, for example,1,2-phenylenediamine, with an α-haloester, for example ethyl2-bromoisobutyrate, mediated by a base, for examplediisopropylethylamine, to afford a compound of Structure 44. Nitrationof 44 with, for example, nitric acid in sulfuric acid, affords acompound of Structure 45. The nitro group of 45 can be reduced to thecorresponding aniline, with, for example, palladium on carbon under ahydrogen atmosphere, to afford a compound of Structure 46. Treatment ofthe aniline with a β-ketoester or its corresponding hydrate, for example4,4,4-trifluoroacetoacetate, at elevated temperatures, affords thecorresponding acetanilide. Treatment of the acetanilide with an acid,for example, sulfuric acid, affords a compound of Structure 47.Protection of the pyridone ring, with, for example isopropyl iodidemediated by a base, for example, cesium fluoride, affords thecorresponding imino ether (Structure 48). Reduction of the amide with,for example, borane dimethyl sulfide, affords the corresponding amine.Hydrolysis of this imino ether with an acid, for example, hydrochloricacid in acetic acid, affords a pyrazino-quinolinone compound such asStructure 49.

[0142] Thiazino-quinolinone compounds (e.g., Structure 56) are preparedas shown in Scheme XI. The process of Scheme XI begins with thetreatment of an aniline, for example, 4-bromo-3-chloroaniline, with aβ-ketoester or its corresponding hydrate, for example4,4,4-trifluoroacetoacetate, at elevated temperatures, to afford thecorresponding acetanilide. Treatment of the acetanilide with an acid,for example, sulfuric acid, affords the corresponding 1H-quinolin-2-one(an example of a Knorr cyclization as described further herein).Protection of the pyridonering, with, for example, isopropyl iodide,mediated by a base, for example, cesium fluoride, affords a compound ofStructure 51. Treatment of a compound (e.g., Structure 51) with aβ-aminothiol, for example, 2-aminoethanethiol hydrochloride, mediated bya base, for example, sodium hydride, affords a compound of Structure 52.Treatment of a compound of Structure 52 with a ligated transition metal,for example palladium acetate and BINAP, in the presence of a base, forexample sodium t-butoxide, at elevated temperatures, affords a compoundof Structure 53. See S. Wagaw, et al., J. Am. Chem. Soc. 1997, 119,8451-8458. Treatment of a compound of Structure 53 with an aldehyde orits corresponding hydrate or hemiacetal, for example, formaldehyde,affords a compound of Structure 55. Hydrolysis of the imino ether can beaccomplished by treatment of a compound of Structure 55 with an acid,for example hydrochloric acid, at elevated temperatures, to afford athiazino-quinolinone compound such as Structure 56. Alternatively, acompound of Structure 53 can be deprotected with an acid, for examplehydrochloric acid, at elevated temperatures, to afford athiazino-quinolinone compound such as Structure 54.

[0143] The compounds of the present invention also include racemates,stereoisomers and mixtures of said compounds, includingisotopically-labeled and radio-labeled compounds. Such isomers can beisolated by standard resolution techniques, including fractionalcrystallization and chiral column chromatography.

[0144] As noted above, any of the steroid modulator compounds of thepresent invention can be combined in a mixture with a pharmaceuticallyacceptable carrier to provide pharmaceutical compositions useful fortreating the biological conditions or disorders noted herein inmammalian, and more preferably, in human patients. The particularcarrier employed in these pharmaceutical compositions may take a widevariety of forms depending upon the type of administration desired,e.g., intravenous, oral, topical, suppository or parenteral.

[0145] In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like will be employed. Due totheir ease of administration, tablets and capsules represent the mostadvantageous oral dosage form for the pharmaceutical compositions of thepresent invention.

[0146] For parenteral administration, the carrier will typicallycomprise sterile water, although other ingredients that aid insolubility or serve as preservatives, may also be included. Furthermore,injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like will be employed.

[0147] For topical administration, the compounds of the presentinvention may be formulated using bland, moisturizing bases, such asointments or creams. Examples of suitable ointment bases are petrolatum,petrolatum plus volatile silicones, lanolin, and water in oil emulsionssuch as Eucerin™ (Beiersdorf). Examples of suitable cream bases areNivea™ Cream (Beiersdorf), cold cream (USP), Purpose Cream™ (Johnson &Johnson), hydrophilic ointment (USP), and Lubriderm™ (Warner-Lambert).

[0148] The pharmaceutical compositions and compounds of the presentinvention will generally be administered in the form of a dosage unit(e.g., tablet, capsule etc.) at from about 1 μg/kg of body weight toabout 500 mg/kg of body weight, more preferably from about 10 μg/kg toabout 250 mg/kg, and most preferably from about 20 μg/kg to about 100mg/kg. As recognized by those skilled in the art, the particularquantity of pharmaceutical composition according to the presentinvention administered to a patient will depend upon a number offactors, including, without limitation, the biological activity desired,the condition of the patient, and tolerance for the drug.

[0149] The compounds of this invention also have utility when radio- orisotopically-labeled as ligands for use in assays to determine thepresence of AR in a cell background or extract. They are particularlyuseful due to their ability to selectively activate androgen receptors,and can therefore be used to determine the presence of such receptors inthe presence of other steroid receptors or related intracellularreceptors.

[0150] Due to the selective specificity of the compounds of thisinvention for steroid receptors, these compounds can be used to purifysamples of steroid receptors in vitro. Such purification can be carriedout by mixing samples containing steroid receptors with one or more ofthe compounds of the present invention so that the compounds bind to thereceptors of choice, and then separating out the bound ligand/receptorcombination by separation techniques which are known to those of skillin the art. These techniques include column separation, filtration,centrifugation, tagging and physical separation, and antibodycomplexing, among others.

[0151] The compounds and pharmaceutical compositions of the presentinvention can advantageously be used in the treatment of the diseasesand conditions described herein. In this regard, the compounds andcompositions of the present invention will prove particularly useful asmodulators of male sex steroid-dependent diseases and conditions such asthe treatment of acne, male-pattern baldness, male hormone replacementtherapy, sexual dysfunction, wasting diseases, hirsutism, stimulation ofhematopoiesis, hypogonadism, prostatic hyperplasia, osteoporosis, malecontraception, impotence, cancer cachexia, various hormone-dependentcancers, including, without limitation, prostate and breast cancer andas anabolic agents.

[0152] The compounds and pharmaceutical compositions of the presentinvention possess a number of advantages over previously identifiedsteroidal and non-steroidal compounds.

[0153] Furthermore, the compounds and pharmaceutical compositions of thepresent invention possess a number of advantages over previouslyidentified steroid modulator compounds. For example, the compounds areextremely potent activators of AR, preferably displaying 50% maximalactivation of AR at a concentration of less than 100 nM, more preferablyat a concentration of less than 50 nM, more preferably yet at aconcentration of less than 20 nM, and most preferably at a concentrationof 10 nM or less. Also, the selective compounds of the present inventiongenerally do not display undesired cross-reactivity with other steroidreceptors, as is seen with the compound mifepristone (RU486; RousselUclaf), a known PR antagonist that displays an undesirable crossreactivity on GR and AR, thereby limiting its use in long-term, chronicadministration. In addition, the compounds of the present invention, assmall organic molecules, are easier to synthesize, provide greaterstability and can be more easily administered in oral dosage forms thanother known steroidal compounds.

[0154] The invention will be further illustrated by reference to thefollowing non-limiting Examples.

EXAMPLE 11,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 101, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=H)

[0155] General Method 1: Cyclization of an α-chloroacetyl chloride to2-amino-5-nitrophenol. To a solution of 2-amino-5-nitrophenol (1.0equiv), NaHCO₃ (2.4 equiv) in 4-methyl-2-pentanone (0.6 mL/mmol) andwater (0.6 mL/mmol) was added an α-chloroacetyl chloride derivative(1.15 equiv) via syringe pump over 45 min at 0° C. The reaction mixturewas allowed to warm to room temperature and then refluxed overnight. Thecrude reaction mixture was allowed to cool to room temperature, filteredand washed with water (3×1.2 mL/mmol) to afford the desired product as atan solid.

[0156] 7-Nitro-2H-1,4-benzoxazin-3(4H)-one (Structure 2 of Scheme I,where R⁶=H).

[0157] This compound was prepared by General Method 1 from2-amino-5-nitrophenol (6.0 g, 39 mmol), NaHCO₃ (7.8 g, 93 mmol), andchloroacetyl chloride (3.58 mL, 45 mmol) to afford 6.91 g (91%) of7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data for7-nitro-2H-1,4-benzoxazin-3(4H)-one: R_(f) 0.44 (11.5:1 CH₂Cl₂:MeOH); ¹HNMR (400 MHz, DMSO-d₆) δ 11.31 (br s, 1H), 7.90 (dd, 1H, J=8.7, 2.6),7.76 (d, 1H, J=2.5), 7.06 (d, 1H, J=8.7), 4.73 (s, 2H).

[0158] General Method 2: Reduction of an amide Structure 2 to an amineof Structure 3. To a solution of a 2H-1,4-benzoxazin-3(4H)-one ofStructure 2 (1.0 equiv) in THF (10 mL/mmol) was added boranedimethylsulfide (2.0 M or 10.0 M in THF, 4 equiv) at rt, then thesolution was heated to reflux for 16-18 hrs. The mixture was cooled toroom temperature, quenched slowly with methanol until gas evolutionstops, then refluxed for an additional 30 min. The solvent was removedunder reduced pressure and the compound purified by flash chromatographyas indicated.

[0159] 3,4-Dihydro-7-nitro-2H-1,4-benzoxazine (Structure 3 of Scheme I,where R⁶=H). This compound was prepared by General Method 2 from7-nitro-2H-1,4-benzoxazin-3(4H)-one (2.0 g, 10 mmol) and boranedimethylsulfide (2.0 M in THF, 24 mL, 48 mmol) and purified on silicagel (20:1 CH₂Cl₂:MeOH) to afford 1.84 g (98%) of3,4-dihydro-7-nitro-2H-1,4-benzoxazine, an orange solid. Data for3,4-dihydro-7-nitro-2H-1,4-benzoxazine: R_(f)0.76 (11.5:1 CH₂Cl₂:MeOH);¹H NMR (400 MHz, CDCl₃) δ 7.74 (dd, 1H, J=8.7, 2.5), 7.69 (d, 1H,J=2.5), 6.52 (d, 1H, J=8.7), 4.56 (br s, 1H), 4.26 (t, 2H, J=4.4), 3.54(td, 2H, J=4.4, 2.5)

[0160] General Method 3: Reductive amination of a3,4-dihydro-2H-1,4-benzoxazine derivative with sodium cyanoborohydridein acetic acid. To a solution of a3,4-dihydro-7-nitro-2H-1,4-benzoxazine (1.0 equiv) in acetic acid (7.8mL/mmol) was added an aldehyde component (10 equiv) and the mixture wasstirred at rt for 1 h. To this mixture was added portionwise sodiumcyanoborohydride (4.8 equiv) and stirred at room temperature overnight.The resulting mixture was poured over ice and neutralized with 6M NaOHto pH 7.0, extracted with CH₂Cl₂ (3×30 mL/mmol), washed with pH 7phosphate buffer (50 mL/mmol) and brine (50 mL/mmol). The organicsolution was dried (MgSO₄) and concentrated under reduced pressure toafford the desired product as a yellow solid.

[0161] 3,4-Dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine (Structure 4 ofScheme I, where R⁶=H, R^(x)=H). This compound was prepared by GeneralMethod 3 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (1.15 g, 6.38mmol), paraformaldehyde (1.92 g, 64.1 mmol) and NaBH₃CN (1.95 g, 30.9mmol) to afford 1.21 g (98%) of3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine, a yellow solid. Datafor 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine: R_(f)0.83 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl3) δ 7.82 (dd, 1H, J=9.0, 2.6), 7.65(d, 1H, J=3.4), 6.56 (d, 1H, J=8.9), 4.27 (t, 2H, J=4.6), 3.46 (t, 2H,J=4.5), 3.05 (s, 3H).

[0162] General Method 4: Hydrogenation of a4-alkyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine. To a solution of a4-alkyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine in 1:1 EtOAc:EtOH (13mL/mmol) was added 10% Pd—C (6% by wt). The flask was flushed andevacuated with N₂ (3×), then stirred under an atmosphere of H₂overnight. The reaction mixture was filtered through Celite, washed withEtOAc (2×20 mL/mmol) and concentrated under reduced pressure to give thedesired product as a light purple/tan solid, which was purified onsilica gel as indicated.

[0163] 7-Amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine. (Structure 5 ofScheme I, where R⁶=H, R^(x)H). This compound was prepared by GeneralMethod 4 from 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine (262 mg,1.35 mmol) and purified by flash chromatography (CH₂Cl₂/MeOH, 20:1) toafford 167 mg (75%) of 7-amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine.Data for 7-amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine: R_(f)0.36(11.5:1 CH₂Cl₂:MeOH) ¹H NMR (400 MHz, CDCl₃) δ 6.55 (d, 1H, J=8.2), 6.25(d, 1H, J=2.6), 6.22 (dd, 1H, J=7.0, 2.7), 4.28 (t, 2H, J=4.4), 3.32 (brs, 2H), 3.13 (t, 2H, J=4.5), 2.79 (s, 3H).

[0164] General Method 5: Condensation of a7-amino-3,4-dihydro-2H-1,4-benzoxazine with acetoacetates or theircorresponding hydrates followed by Knorr reaction mediated bypolyphosphoric acid. To a solution of a7-amino-3,4-dihydro-2H-1,4-benzoxazine of Structure 5 (1.0 equiv) inbenzene (10 mL/mmol) under N₂ at room temperature was added anacetoacetate derivative (1.2 equiv) and the reaction was heated atreflux for 12-16 hrs, whereupon the mixture was concentrated underreduced pressure. The crude reaction mixture was diluted inpolyphosphoric acid (8 mL/mmol) and heated to 100° C. for 12-16 hrs. Theresulting mixture was poured over ice and neutralized with 6M NaOHsolution to pH 7.0, extracted with CH₂Cl₂ (3×30 mL/mmol), washed with pH7 phosphate buffer (50 mL/mmol) and brine (50 mL/mmol). The organicsolution was dried (MgSO₄) and concentrated under reduced pressure.Purification by flash chromatography (silica gel, 20:1, CH₂Cl₂/MeOH)afforded the desired quinolone as a fluorescent-yellow solid.

[0165]1,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 101, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=H). This compound was prepared by General Method 5 from7-amino-3,4-dihydro-4-methyl-2H-1,4-benzoxazine (162 mg, 0.98 mmol), andethyl 4,4,4-trifluoroacetoacetate (0.19 mL, 1.28 mmol) and purified byflash chromatography (19:1 CH ₂Cl₂:MeOH) to afford 125 mg (44%) ofCompound 101. Data for Compound 101: R_(f)0.44 (EtOAc); ¹H NMR (400 MHz,CDCl₃) δ 10.65 (br s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H),4.39 (t, 2H, J=4.6), 3.31 (t, 2H, J=4.5), 2.94 (s, 3H).

EXAMPLE 21,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 102, Structure 7 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=H)

[0166] General Method 6: N-Methylation of a pyridone (compounds ofStructure 6) to form a compound of Structure 7. To an oven-dried rbflask containing a pyridone of Structure 6 (1.0 equiv) in THF (5mL/mmol) was added portionwise sodium hydride (60% dispersion in mineraloil, 1.2 equiv) under N₂. After 30 min, iodomethane (1.2 equiv) wasadded and the mixture was allowed to stir under N₂ an additional 8-10hrs. The reaction mixture was then diluted with pH 7 phosphate buffer(50 mL/mmol), extracted with CH₂Cl₂ (3×30 mL) and washed with brine (50mL/mmol). The organic solution was dried (MgSO₄) and concentrated underreduced pressure. Purification by flash chromatography (silica gel,20:1, CH₂Cl₂:MeOH) afforded the desired product as a fluorescent-yellowsolid.

[0167]1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 102, Structure 7 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=H). This compound was prepared by General Method 6 from3,4-dihydro-4-methyl-6-(trifluoromethyl)-8-pyridono-[5,6-g]-2H-1,4-benzoxazine(23.9 mg, 0.08 mmol), iodomethane (6.3 μL, 0.10 mmol) and sodium hydride(4.0 mg, 0.10 mmol) and purified by flash chromatography (19:1CH₂Cl₂:MeOH) to afford 13.7 mg (55%) of Compound 102. Data for Compound102: R_(f)0.54 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 6.96 (s,1H), 6.95 (s, 1H), 6.93 (s, 1H), 4.42 (t, 2H, J=4.4), 3.66 (s, 3H), 3.31(t, 2H, J=4.6), 2.95 (s, 3H).

EXAMPLE 31-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 103, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=CH₃)

[0168] 4-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (Structure 4 ofScheme I, where R⁶=H, R^(x)=CH₃). This compound was prepared by GeneralMethod 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine(EXAMPLE 1) (1.15 g, 6.39 mmol), acetaldehyde (3.59 mL, 64.2 mmol) andNaBH₃CN (1.95 g, 31 mmol) to afford 984 mg (74%) of4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: R_(f)0.85 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, 1H, J=9.6, 2.6), 7.66(d, 1H, J=2.7), 6.29 (d, 1H, J=9.2), 4.23 (t, 2H, J=4.7), 3.47 (t, 2H,J=4.7), 3.45 (q, 2H, J=7.2), 1.22 (t, 3H, J=7.0).

[0169] 7-Amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine (Structure 5 ofScheme I, where R⁶=H, R^(x)=CH₃). This compound was prepared by GeneralMethod 4 (EXAMPLE 1) from 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine(264 mg, 1.3 mmol) and purified by flash chromatography (CH₂Cl₂/MeOH,20:1) to afford 173 mg (77%) of7-amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine. Data for7-amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine: R_(f)0.52 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 6.56 (d, 1H, J=8.1), 6.26-6.22(m, 2H), 4.23 (t, 2H, J=4.4), 3.29 (br s, 2H), 3.24 (q, 2H, J=7.1), 3.19(t, 2H, J=4.4), 1.11 (t, 3H, J=7.0).

[0170]1-Ethyl-1,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 103, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=CH₃). This compound was prepared by General Method 5(EXAMPLE 1) from 7-amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine (170 mg,0.95 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.16 mL, 1.14 mmol)and purified by flash chromatography (19:1 CH₂Cl₂:MeOH) to afford 100 mg(35%) of Compound 103. Data for Compound 103: R_(f)0.21 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 11.47 (br s, 1H), 6.92 (s, 1H),6.88 (s, 1H), 6.81 (s, 1H), 4.35 (t, 2H, J=4.5), 3.4 (q, 2H, J=7.1),3.34 (t, 2H, J=4.5), 1.19 (t, 3H, J=7.1). Anal. Calcd for C₁₄H₁₃F₃N₂O₂:C, 56.38; H, 4.39; N, 9.39. Found: C, 56.04; H, 4.32; N, 9.22.

EXAMPLE 4

[0171]1-Ethyl-1,2,3,6-tetrahydro-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 104, Structure 7 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=CH₃). This compound was prepared by General Method 6(EXAMPLE 2) from Compound 103 (18.5 mg, 0.06 mmol), iodomethane (5.8 μL,0.09 mmol) and sodium hydride (3.6 mg, 0.09 mmol) and purified by flashchromatography (19:1 CH₂Cl₂:MeOH) to afford 13.5 mg (71%) of Compound104. Data for Compound 104: R_(f) 0.57 (2:3 EtOAc:hexanes); ¹H NMR (400MHz, CDCl₃) δ 6.98 (s, 1H), 6.93 (s, 1H), 6.85 (s, 1H), 4.38 (t, 2H,J=4.5), 3.66 (s, 3H), 3.4 (q, 2H, J=7.1), 3.35 (t, 2H, J=4.6), 1.19 (t,3H, J=7.1).

EXAMPLE 51,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 105, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=CF₃)

[0172] General Method 7: Reductive amination of a7-nitro-2H-1,4-benzoxazine in trifluoroacetic acid. To a solution of a7-nitro-3,4-dihydro-2H-1,4-benzoxazine (1.0 equiv) in trifluoroaceticacid (0.5 mL/mmol) was added an aldehyde or its corresponding hydrate(10 equiv) and the mixture was stirred at rt for 2 h. To this mixturewas added portionwise sodium cyanoborohydride (4.8 equiv) and stirred atroom temperature overnight. The resulting mixture was poured over iceand neutralized with 6M NaOH solution to pH 7.0, extracted with CH₂Cl₂(3×30 mL/mmol), washed with pH 7 phosphate buffer (50 mL/mmol) and brine(50 mL/mmol). The organic solution was dried (MgSO₄) and concentratedunder reduced pressure to afford the desired product as a yellow solid.

[0173] 3,4-Dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=H, R^(x)=CF₃). This compound wasprepared by General Method 7 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine(EXAMPLE 1) (388 mg, 2.1 mmol), 2,2,2-trifluoroacetaldehyde monohydrate(2.51 g, 21.6 mmol) and NaBH₃CN (656 mg, 10.4 mmol) to afford 500 mg(88%) of3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, ayellow solid. Data for3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.59 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, 1H,J=8.8, 2.6), 7.72 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.1), 4.27 (t, 2H,J=4.5), 3.94 (q, 2H, J=8.6), 3.61 (t, 2H, J=4.5).

[0174] 7-Amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 5 of Scheme I, where R⁶=H, R^(x)=CF₃). This compound wasprepared by General Method 4 (EXAMPLE 1) from3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (3.12 g,12 mmol) and purified by flash chromatography (CH₂Cl₂/MeOH, 20:1) toafford 2.7 g (98%) of7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine. Datafor 7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f) 0.47 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.56 (d, 1H,J=8.2), 6.30-6.20 (m, 2H), 4.16 (t, 2H, J=4.3), 3.65 (q, 2H, J=9.1),3.39 (t, 2H, J=4.4), 3.36 (br s, 1H).

[0175]1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 105, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=CF₃). This compound was prepared by General Method 5(EXAMPLE 1) from 7-amino-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(2.7 g, 11.6 mmol), and ethyl 4,4,4-trifluoroacetoacetate (2.04 mL, 14mmol) and purified by flash chromatography (3:2 EtOAc:hexanes) andrecrystallized from MeOH to afford 790 mg (19%) of Compound 105. Datafor Compound 105: R_(f)0.25 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz,CDCl₃) δ 11.95 (br s, 1H), 7.04 (br s, 1H), 6.91 (s, 1H), 6.90 (s, 1H),4.33 (t, 2H, J=4.5), 3.88 (q, 2H, J=8.9), 3.56 (t, 2H, J=4.5). Anal.Calcd for C₁₄H₁₀F₆N₂O₂: C, 47.74; H, 2.86; N, 7.95. Found: C, 47.81; H,2.80; N, 7.87.

EXAMPLE 6

[0176]8-Fluoro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 106, Structure 6 of Scheme I, where R¹=F, R²=trifluoromethyl,R⁶=H, R^(x)=CF₃). This compound was prepared by General Method 5(EXAMPLE 1) from7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (EXAMPLE5) (24 mg, 0.1 mmol), and ethyl2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (27 mg, 0.12 mmol) andpurified by flash chromatography (1:1 EtOAc:hexanes) to afford 8 mg(21%) of Compound 106. Data for Compound 106: R_(f) 0.15 (19:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 11.38 (br s, 1H), 7.08 (s, 1H),6.86 (s, 1H), 4.32 (t, 2H, J=4.5), 3.88 (q, 2H, J=8.8), 3.56 (t, 2H,J=4.4)

EXAMPLE 7

[0177]8-Chloro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 107, Structure 6 of Scheme I, where R¹=Cl, R²=trifluoromethyl,R⁶=H, R^(x)=CF₃). This compound was prepared by General Method 5(EXAMPLE 1) from7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (EXAMPLE5) (21 mg, 0.1 mmol), and ethyl 2-chloro-4,4,4-trifluoroacetoacetate (23mg, 0.1 mmol) and purified by reverse phase HPLC (ODS, 75:25 MeOH:water,3 mL/min) to afford 2 mg (6%) of Compound 107. Data for Compound 107:R_(f)0.12 (19:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 10.22 (br s,1H), 7.15 (s, 1H), 6.75 (s, 1H), 4.33 (t, 2H, J=4.5), 3.87 (q, 2H,J=8.7), 3.56 (t, 2H, J=4.4).

EXAMPLE 8

[0178]9-(Difluoromethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 108, Structure 6 of Scheme I, where R¹=H, R²=difluoromethyl,R⁶=H, R^(x)=CF₃). This compound was prepared by General Method 5(EXAMPLE 1) from7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (EXAMPLE5) (310 mg, 1.3 mmol), and ethyl 4,4-difluoroacetoacetate (243 mg, 1.5mmol) and purified by flash chromatography (19:1 CH₂Cl₂:MeOH) to afford50 mg (11%) of Compound 108. Data for Compound 108: R_(f)0.22 (3:2EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) 10.92 (br s, 1H), 7.06 (s, 1H),6.82 (s, 1H), 6.72 (t, 1H, J=54.2), 6.71 (s, 1H), 4.32 (t, 2H, J=4.4),3.85 (q, 2H, J=8.9), 3.54 (t, 2H, J=4.4).

EXAMPLE 9

[0179]1,2,3,6-Tetrahydro-6-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 109, Structure 7 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=CF₃). This compound was prepared by General Method 6(EXAMPLE 2) from Compound 105 (EXAMPLE 5) (85.0 mg, 0.24 mmol),iodomethane (18 μL, 0.29 mmol) and sodium hydride (11.6 mg, 0.29 mmol)and purified by flash chromatography (3:2 EtOAc:hexanes) to afford 73 mg(83%) of Compound 109. Data for Compound 109: R_(f)0.47 (3:2EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) 7.09 (s, 1H), 6.95 (s, 1H), 6.89(s, 1H), 4.36 (t, 2H, J=4.4), 3.88 (q, 2H, J=8.9), 3.66 (s, 3H), 3.57(t, 2H, J=4.4).

EXAMPLE 9A

[0180]7-Chloro-2,3-dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Compound 109A, Structure 7A of Scheme I, where R¹=H,R²=trifluoromethyl, R⁶=H, R^(x)=CF₃, R^(A)=Cl). A solution of Compound105 (EXAMPLE 5) (25 mg, 0.07 mmol) in 3 mL POCl₃ was heated at 80° C.for 2 h. The reaction was quenched with NaHCO₃ (sat'd) in ice andneutralized to pH=7. The mixture was extracted with CH₂Cl₂, and theorganic layers were washed with brine, dried over MgSO4, filtered, andconcentrated. Flash chromatography (95:5 CH₂Cl₂:MeOH) afforded 20 mg(77%) of Compound 109A, a yellow solid. Data for Compound 109A: ¹H NMR(400 MHz, CDCl₃) 7.48 (s, 1H), 7.46 (s, 1H), 7.16 (s, 1H), 4.38 (t, 2H,J=4.6), 4.00 (q, 2H, J=8.8), 3.66 (t, 2H, J=4.4).

EXAMPLE 101,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-thione(Compound 110, Structure 8 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=CF₃)

[0181] General Method 8: Conversion of a pyridone to a thiopyridone. Toa solution of a pyridone of Structure 6 (1.0 equiv) in benzene (0.6mL/mmol) was added Lawesson's reagent (1.0 equiv) and heated to 60° C.for 12-16 hours. The reaction mixture was allowed to cool to roomtemperature, partitioned with H₂O/ether (200 mL/100 mL), extracted withether (2×30 mL), and washed with brine (50 mL/mmol). The organicsolution was dried (MgSO₄) and concentrated under reduced pressure togive the desired product as an orange solid, which was purified onsilica gel as indicated.

[0182]1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-thione(Compound 110, Structure 8 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=CF₃). This compound was prepared by General Method 8 fromCompound 105 (EXAMPLE 5) (50.0 mg, 0.15 mmol) and Lawesson's reagent(57.0 mg, 0.15 mmol) and purified by flash chromatography (19:1CH₂Cl₂:MeOH) to afford 12 mg (23%) of Compound 110. Data for Compound110: ¹H NMR (400 MHz, CDCl₃) 11.47 (br s, 1H), 7.04 (s, 2H), 6.91 (s,1H), 4.35 (t, 2H, J=4.6), 3.97 (q, 2H, J=8.8), 3.63 (t, 2H, J=4.6).

EXAMPLE 111,2,3,6-Tetrahydro-1-propyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 111, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=CH₃CH₂)

[0183] 7-Nitro-4-propyl-2H-1,4-benzoxazine (Structure 4 of Scheme I,where R⁶=H, R^(x)=CH₃CH₂). This compound was prepared by General Method3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1)(530 mg, 2.9 mmol), propionaldehyde (1.61 g, 28 mmol) and NaBH₃CN (872mg, 14 mmol) to afford 450 mg (69%) of3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine, an orange oil. Data for3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine: R_(f)0.57 (2:1EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, 1H, J=9.1, 2.6),7.66 (d, 1H, J=2.6), 6.56 (d, 1H, J=9.0), 4.22 (t, 2H, J=4.5), 3.49 (t,2H, J=4.5), 3.33 (t, 2H, J=7.5), 1.67 (sext, 2H, J=7.4), 0.98 (t, 3H,J=7.4).

[0184] 7-Amino-3,4-dihydro-4-propyl-2H-1,4-benzoxazine (Structure 5 ofScheme I, where R⁶=H, R^(x)=CH₃CH₂). This compound was prepared byGeneral Method 4 (EXAMPLE 1) from3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine (50 mg, 0.2 mmol) andpurified by flash chromatography (CH₂Cl₂/MeOH, 20:1) to afford 36 mg(84%) of 7-amino-3,4-dihydro-4-propyl-2H-1,4-benzoxazine. Data for7-amino-3,4-dihydro-4-propyl-2H-1,4-benzoxazine: R_(f)0.43 (2:1EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.53 (d, 1H, J=8.9), 6.25-6.20(m, 2H), 4.21 (t, 2H, J=4.4), 3.28 (br s, 2H), 3.21 (t, 2H, J=4.4), 3.08(t, 2H, J=7.5), 1.60 (sext, 2H, J=7.4), 0.94 (t, 3H, J=7.4).

[0185]1,2,3,6-Tetrahydro-1-propyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 111, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=CH₃CH₂). This compound was prepared by General Method 5(EXAMPLE 1) from 7-amino-3,4-dihydro-4-propyl-2H-1,4-benzoxazine (395mg, 2.0 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.36 mL, 2.5 mmol)and purified by flash chromatography (3:2 EtOAc:hexanes) andrecrystallized from MeOH to afford 100 mg (16%) of Compound 111. Datafor Compound 111: R_(f)0.24 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃)11.79 (br s, 1H), 6.88 (s, 1H), 6.87 (s, 1H), 6.83 (s, 1H), 4.32 (t, 2H,J=4.5), 3.37 (t, 2H, J=4.5), 3.26 (t, 2H, J=7.4), 1.66 (sext, 2H,J=7.4), 0.99 (t, 3H, J=7.4).

EXAMPLE 121,2,3,6-Tetrahydro-1-isobutyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 112, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=H, R^(x)=(CH₃)₂CH).

[0186] 3,4-Dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine (Structure 4 ofScheme I, where R⁶=H, R^(x)=(CH₃)₂CH). This compound was prepared byGeneral Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine(EXAMPLE 1) (550 mg, 3.0 mmol), isobutyraldehyde (1.65 g, 22.8 mmol) andNaBH₃CN (959 mg, 15 mmol) to afford 713 mg (99%) of3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine, an yellow solid. Datafor 3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine: R_(f) 0.75 (3:2EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, 1H, J=9.0, 2.6),7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.21 (t, 2H, J=4.5), 3.52 (t,2H, J=4.6), 3.16 (d, 2H, J=7.4), 3.12 (hept, 1H, J=6.9), 0.97 (d, 6H,J=6.7).

[0187] 7-Amino-3,4-dihydro-4-isobutyl-2H-1,4-benzoxazine (Structure 5 ofScheme I, where R⁶=H, R^(x)=CH₃)₂CH). This compound was prepared byGeneral Method 4 (EXAMPLE 1) from3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine (712 mg, 3.0 mmol) andpurified by flash chromatography (CH₂Cl₂/MeOH, 20:1) to afford 621 mg(99%) of 7-amino-4-isobutyl-2H-1,4-benzoxazine. Data for7-amino-3,4-dihydro-4-isobutyl-2H-1,4-benzoxazine: R_(f)0.43 (3:2EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.49 (d, 1H, J=9.1), 6.23 (m,2H), 4.20 (t, 2H, J=4.4), 3.28 (br s, 2H), 3.23 (t, 2H, J=4.4), 2.85 (d,2H, J=7.2), 2.04-1.92 (m, 1H), 0.94 (d, 6H, J=6.5).

[0188]1,2,3,6-Tetrahydro-1-isobutyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 112, Structure 7 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=(CH₃)₂CH). This compound was prepared by General Method 5(EXAMPLE 1) from 7-amino-3,4-dihydro-4-isobutyl-2H-1,4-benzoxazine (620mg, 3.0 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.527 mL, 3.6mmol) and purified by flash chromatography (3:2 EtOAc:hexanes) andrecrystallized from MeOH to afford 241 mg (25%) of Compound 112. Datafor Compound 112: R_(f)0.2 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃)δ 10.62 (br s, 1H), 6.87 (s, 2H), 6.74 (s, 1H), 4.31 (t, 2H, J=4.5),3.41 (t, 2H, J=4.5), 3.05 (d, 2H, J=7.0), 2.05-1.95 (m, 1H), 0.98 (d,6H, J=6.5).

EXAMPLE 13

[0189]1,2,3,6-Tetrahydro-1-isobutyl-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 113, Structure 7 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=H, R^(x)=(CH₃)₂CH). This compound was prepared by General Method 6(EXAMPLE 2) from Compound 112 (10.0 mg, 0.03 mmol), iodomethane (3.0 μL,0.03 mmol) and sodium hydride (1.5 mg, 0.03 mmol) and purified by flashchromatography (19:1 CH₂Cl₂:MeOH) to afford 8.3 mg (80%) of Compound113. Data for Compound 113: ¹H NMR (400 MHz, CDCl₃) δ 6.93 (s, 2H), 6.85(s, 1H), 4.34 (t, 2H, J=4.5), 3.65 (s, 3H), 3.43 (t, 2H, J=4.5), 3.06(d, 2H, J=7.2), 2.09 (m, 1H), 0.99 (d, 6H, J=6.6).

EXAMPLE 14(±)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 114, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Me, R^(x)=CF₃)

[0190] (±)-2-Methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (Structure 2 ofScheme I, where R⁶=Me). This compound was prepared by General Method 1(EXAMPLE 1) from 2-amino-5-nitrophenol (3.0 g, 20 mmol), NaHCO₃ (3.9 g,46 mmol), and 2-chloropropionyl chloride (2.2 mL, 22 mmol) to afford 3.1g (77%) of (±)-2-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data for(±)-2-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one: R_(f)0.45 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, DMSO) δ 11.28 (br s, 1H), 7.92 (dd, 1H,J=8.6, 2.2), 7.77 (d, 1H, J=2.6), 7.07 (d, 1H, J=8.7), 4.85 (q, 1H,J=6.7), 1.46 (d, 3H, J=6.8).

[0191] (±)-3,4-Dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine (Structure 3of Scheme I, where R⁶=Me). This compound was prepared by General Method2 (EXAMPLE 1) from (±)-2-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.8g, 8.6 mmol) and borane dimethylsulfide (10.0-10.2 M in THF, 3.5 mL, 35mmol) and purified on silica gel (20:1 CH₂Cl₂:MeOH) to afford 1.57 g(94%) of 3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine, an orangesolid. Data for 3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine:R_(f)0.75 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 7.73 (dd, 1H,J=8.7, 2.6), 7.69 (d, 1H, J=2.2), 6.52 (d, 1H, 8.7), 4.56 (br s, 1H),4.20 (m, 1H), 3.47 (ddd, 1H, J=12.1, 3.8, 2.7), 3.21 (ddd, 1H, J=12.0,8.1, 1.2), 1.40 (d, 3H, J=6.1).

[0192](±)-3,4-Dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=Me, R^(x)=CF₃). This compound wasprepared by General Method 7 (EXAMPLE 5) from(±)-3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine (400 mg, 2.0 mmol),2,2,2-trifluoroacetaldehyde monohydrate (2.4 g, 20.6 mmol) and NaBH₃CN(628 mg, 10.0 mmol) to afford 550 mg (96%) of(±)-3,4-dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,a yellow solid. Data for(±)-3,4-dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.85 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, 1H,J=9.2, 2.6), 7.72 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.1), 4.23 (m, 1H),4.23-3.82 (m, 2H), 3.47 (dd, 1H, J=12.1, 2.6), 3.37 (dd, 1H, J=12.2,8.2), 1.41 (d, 3H, J=6.1).

[0193](±)-7-Amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 5 of Scheme I, where R⁶=Me, R^(x)=CF₃). This compound wasprepared by General Method 4 (EXAMPLE 1) from(±)-3,4-dihydro-2-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(394 mg, 1.4 mmol) and purified by flash chromatography (CH₂Cl₂/MeOH,20:1) to afford 345 mg (98%) of(±)-7-amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine.Data for(±)-7-amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.60 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 6.57 (d, 1H,J=9.2), 6.27-6.22 (m, 2H), 6.24 (s, 1H), 4.18 (m, 1H), 3.75-3.62 (m,3H), 3.27 (dd, 1H, J=12.0, 9.8), 3.10 (dd, 1H, J=12.0, 8.5), 1.34 (d,3H, J=6.3).

[0194](±)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 114, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=Me, R^(x)=CF₃). This compound was prepared by General Method 5(EXAMPLE 1) from(±)-7-amino-3,4-dihydro-2-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(345 mg, 1.4 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.24 mL, 1.6mmol) and purified by flash chromatography (19:1 CH₂Cl₂:MeOH) to afford52 mg (34%) of Compound 114. Data for Compound 114: R_(f) 0.26 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 10.84 (br s, 1H), 7.05 (s, 1H),6.90 (s, 1H), 6.82 (s, 1H), 4.35 (m, 1H), 3.91 (m, 1H), 3.83 (m, 1H),3.44 (dd, 1H, J=12.1, 2.0), 3.21 (dd, 1H, J=11.7, 7.8), 1.42 (d, 3H,J=6.2). Anal. Calcd for C₁₅H₁₂F₆N₂O₂: C, 49.19; H, 3.30; N, 7.65. Found:C, 49.19; H, 3.23; N, 7.54.

EXAMPLE 15(−)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 115, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Me, R^(x)=CF₃) and(+)-1,2,3,6-tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 116, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Me, R^(x)=CF₃)

[0195] General Method 9: Resolution of Compounds of Structure 6, 18, or23 to their corresponding enantiomers via chiral HPLC. A preparativeChiralpak AD column (10 μm particle size, 20×250 mm OR 10×250 mm, DaicelChemical Industries, Ltd.) on a Beckman Gold HPLC was equilibrated withan eluent of hexanes:isopropanol at a flow rate of 4.5-5 mL/min. Asolution of the racemic compound in MeOH, EtOH, or acetone was preparedand injections were monitored to insure that baseline separation isachieved. Compound elution was monitored by-absorbance detection at 254μM. Sequential injections were performed until the specified amountswere obtained. The solvents of the separated enantiomers were removed invacuo. Purity of the collected fractions were verified by injection ofanalytical amounts and in each case only a single enantiomer wasdetected.

(−)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 115, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Me, R^(x)=CF₃) and(+)-1,2,3,6-tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 116, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Me, R^(x)=CF₃)

[0196] This compound was prepared according to General Method 9 fromCompound 114 (10 mg, 0.03 mmol) on a semiprep Chiralpak AD column(10×250 mm) and eluted with hexanes/isopropanol (95:5), to afford 3 mgof Compound 115, a yellow solid, and 2.0 mg of Compound 116, a yellowsolid. Data for Compound 115: HPLC (Chiralpak AD, 4×250 mm, 95:5hexanes:isopropanol, 0.8 mL/min) t_(R) 16.9 min; [α]_(D)=−78 (c=0.18).Data for Compound 116: HPLC (Chiralpak AD, 4×250 mm, 95:5hexanes:isopropanol, 0.8 mL/min) t_(R) 20.0 min; [α]_(D)=+70 (c=0.12).

EXAMPLE 16(±)-1,2,3,6-Tetrahydro-1,3-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinoline-7-one(Compound 117, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Me, R^(x)=H)

[0197] (±)-3,4-Dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=Me, R^(x)=H). This compound wasprepared from General Method 3 (EXAMPLE 1) from(±)-3,4-dihydro-2-methyl-7-nitro-2H-1,4-benzoxazine (150 mg, 0.77 mmol),paraformaldehyde (233 mg, 7.8 mmol) and NaBH₃CN (235 mg, 3.7 mmol) toafford 160 mg (99%) of(±)-3,4-dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine. Data for(±)-3,4-dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine: R_(f)0.77 (3:2EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, H, J=9.1, 2.5), 7.66(d, 1H, J=2.5), 6.55 (d, 1H, J=8.9), 4.26-4.23 (m, 1H), 3.32 (dd, 1H,J=12.1, 2.7), 3.22 (dd, 1H, J=12.0, 8.2), 3.03 (s, 3H), 1.39 (d, 3H,J=6.5).

[0198] (±)-7-Amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine(Structure 5 of Scheme I, where R⁶=Me, R^(x)=H). This compound wasprepared from General Method 4 EXAMPLE 1) from(±)-3,4-dihydro-2,4-dimethyl-7-nitro-2H-1,4-benzoxazine (160 mg, 0.77mmol) and purified by flash chromatography (CH₂Cl₂/MeOH, 20:1) to afford134 mg (97%) of (±)-7-amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine.Data for (±)-7-amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine:R_(f)0.35 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 6.54 (d, 1H,J=8.0), 6.25-6.20 (m, 2H), 4.36-4.33 (m, 1H), 3.31 (br s, 2H), 3.08 (dd,1H, J=11.4, 2.3), 2.82 (dd, 1H, 11.4, 8.2), 2.78 (s, 3H), 1.33 (d, 3H,J=6.2).

[0199](±)-1,2,3,6-Tetrahydro-1,3-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 117, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=Me, R^(x)=H). This compound was prepared by General Method 5(EXAMPLE 1) from (±)-7-amino-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine(75 mg, 0.42 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.07 mL, 0.48mmol) and purified by flash chromatography (19:1 CH₂Cl₂:MeOH) to afford50 mg (40%) of Compound 117. Data for Compound 117: R_(f) 0.42 (11.5:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 11.17 (br s, 1H), 6.88 (s, 1H),6.87 (s, 1H), 6.78 (s, 1H), 4.45 (m, 1H), 3.24 (dd, 1H, J=11.7, 2.5),3.02 (dd, 1H, J=11.5, 8.2), 2.93 (s, 3H), 1.40 (d, 3H, J=6.5).

EXAMPLE 17(±)-3-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 118, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Et, R^(x)=CF₃)

[0200] (±)-2-Ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (Structure 2 ofScheme I, where R⁶=Et). This compound was prepared by General Method 1(EXAMPLE 1) from 2-amino-5-nitrophenol (3.0 g, 19.5 mmol), NaHCO₃ (3.9g, 46.5 mmol), and 2-chlorobutyryl chloride (3.1 g, 22.4 mmol) to afford1.2 g (28%) of (±)-2-ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data for(±)-2-ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one: R_(f)0.48 (19:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (br s, 1H), 7.91 (dd,1H, J=8.7, 2.6), 7.79 (d, 1H, J=2.4), 7.06 (d, 1H, J=8.7), 4.71-4.68 (m,1H), 1.88-1.76 (m, 2H), 1.00 (t, 3H, J=7.2).

[0201] (±)-2-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (Structure 3of Scheme I, where R⁶=Et). This compound was prepared by General Method2 (EXAMPLE 1) from (±)-2-ethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.2g, 5.4 mmol) and borane dimethylsulfide (10.0-10.2 M in THF, 2.2 mL, 22mmol) and purified on silica gel (1.8:1 hexanes:EtOAc) to afford 723 mg(65%) of (±)-2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, an orangesolid. Data for (±)-2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine:R_(f)0.85 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 7.73 (dd, 1H,J=8.5, 2.4), 7.71 (d, 1H, J=2.3), 6.50 (d, 1H, J=8.6), 4.53 (br s, 1H),3.99-3.94 (m, 1H), 3.48 (dd, 1H, J=8.9, 3.0), 3.23 (dd, 1H, J=10.9,8.0), 1.75-1.61 (m, 2H), 1.07 (t, 3H, J=7.5).

[0202](±)-2-Ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=Et, R^(x)=CF₃). This compound wasprepared by General Method 7 (EXAMPLE 5) from(±)-2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (250 mg, 1.2 mmol),2,2,2-trifluoroacetaldehyde monohydrate (1.4 g, 12 mmol) and NaBH₃CN(366 mg, 5.8 mmol) to afford 346 mg (99%) of(±)-2-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine.Data for(±)-2-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f) 0.75 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, 1H,J=8.9, 2.6), 7.73 (d, 1H, J=2.5), 6.70 (d, 1H, J=9.0), 4.03-3.81 (m,3H), 3.48 (dd, 1H, J=12.1, 2.6), 3.99 (dd, 1H, J=12.1, 8.0), 1.80-1.62(m, 2H), 1.08 (t, 3H, J=7.4).

[0203](±)-7-Amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 5 of Scheme I, where R⁶=Et, R^(x)=CF₃,). This compound wasprepared by General Method 4 (EXAMPLE 1) from(±)-2-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(170 mg, 0.6 mmol) and purified by flash chromatography (CH₂Cl₂/MeOH,20:1) to afford 151 mg (99%) of(±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine.Data for(±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f) 0.62 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.56 (d, 1H,J=8.0), 6.25-6.20 (m, 2H), 3.93 (m, 1H), 3.70-3.64 (m, 3H), 3.43 (br s,1H), 3.31 (m, 1H), 3.12 (dd, 1H, J=11.9, 8.1), 1.74-1.59 (m, 2H), 1.04(t, 3H, J=7.5).

[0204](±)-3-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 118, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=Et, R^(x)=CF₃). This compound was prepared by General Method 5(EXAMPLE 1) from(±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(100 mg, 0.38 mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.81 mg,0.44 mmol) and purified by flash chromatography (19:1 CH₂Cl₂:MeOH) toafford 75 mg (51%) of Compound 114. Data for Compound 114: R_(f) 0.18(19:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 12.05 (br s, 1H), 7.03 (s,1H), 6.95 (s, 1H), 6.92 (s, 1H), 4.15-4.05 (m, 1H), 3.98-3.88 (m, 1H),3.88-3.75 (m, 1H), 3.44 (dd, 1H, J=11.8, 2.5), 3.32 (dd, 1H, J=11.9,8.1), 1.76 (m, 1H), 1.68 (m, 1H), 1.09 (t, 3H, J=7.6).

EXAMPLE 18(±)-3-Ethyl-1,2,3,6-tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 119, Structure 6 of Scheme I, where R¹=H, R²=Trifluoromethyl,R⁶=Et, R^(x)=H)

[0205] (±)-2-Ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=Et, R^(x)=H). This compound wasprepared by General Method 3 (EXAMPLE 1) from2-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 17) (120 mg,0.57 mmol), paraformaldehyde (174 mg, 5.8 mmol) and NaBH₃CN (176 mg, 2.8mmol) to afford 127 mg (99%) of2-ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine. Data for2-ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine: R_(f) 0.89(11.5:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, 1H, J=9.0,2.5), 7.67 (d, 1H, J=2.5), 6.54 (d, 1H, J=9.0), 4.01 (m, 1H), 3.34 (dd,1H, J=12.0, 2.7), 3.23 (dd, 1H, J=12.0, 8.1), 3.03 (s, 3H), 1.79-1.72(m, 1H), 1.67-1.60 (m, 1H), 1.07 (t, 3H, J=7.5).

[0206] (±)-7-Amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=Et, R^(x)=H). This compound wasprepared by General Method 4 (EXAMPLE 1) from(±)-2-ethyl-3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzoxazine (130 mg, 0.6mmol) and purified by flash chromatography (CH₂Cl₂/MeOH, 19:1) to afford80 mg (71%) of(±)-7-amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine. Data for(±)-7-amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine: R_(f) 0.5(19;:1 CH₂Cl₂/MeOH); ¹H NMR (400 MHz, CDCl₃) δ 6.53 (dd, 1H, J=9.1,2.7), 6.25-6.20 (m, 2H), 4.11 (m, 1H), 3.10 (dd, 1H, J=11.4, 2.1), 2.84(dd, 1H, J=11.3, 8.1), 2.78 (s, 3H), 1.75-1.70 (band, 1H), 1.64-1.58 (m,1H), 1.03 (t, 2H, J=7.5).

[0207](±)-3-Ethyl-1,2,3,6-tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 119, Structure 6 of Scheme I, where R¹=H, R²=trifluoromethyl,R⁶=Et, R^(x)=H). This compound was prepared by General Method 5(EXAMPLE 1) from(±)-7-amino-2-ethyl-3,4-dihydro-4-methyl-2H-1,4-benzoxazine (80 mg, 0.4mmol), and ethyl 4,4,4-trifluoroacetoacetate (0.92 mg, 0.5 mmol) andpurified by flash chromatography (19:1 CH₂Cl₂:MeOH) to afford 26 mg(20%) of Compound 119. Data for Compound 119: R_(f) 0.19 (19:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 11.5 (br s, 1H), 6.89 (s, 2H),6.83 (s, 1H), 4.22 (m, 1H), 3.26 (dd, 1H, J=11.6, 2.4), 3.05 (dd, 1H,J=11.6, 8.2), 2.94 (s, 3H), 1.76 (m, 1H), 1.67 (m, 1H), 1.08 (t, 3H,J=7.5).

EXAMPLE 191,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 120, Structure 10 of Scheme II, where R¹=H,R²=Trifluoromethyl)

[0208] 3,4-Dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine(Structure 4 of Scheme I, where R⁶=H, R^(x)=4-anisyl). This compound wasprepared by General Method 3 (EXAMPLE 1) from3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (305 mg, 1.7 mmol),p-anisaldehyde (2.3 g, 17 mmol) and NaBH₃CN (532 mg, 8.4 mmol) to afford361 mg (70%) of3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine, an yellowsolid. Data for3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine: R_(f) 0.79(3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.76 (dd, 1H, J=9.0,2.6), 7.70 (d, 1H, J=2.5), 7.14 (d, 2H, J=8.6), 6.88 (d, 2H, J=8.6),6.63 (d, 1H, J=9.1), 4.54 (s, 2H), 4.26 (t, 2H, J=4.5), 3.80 (s, 3H),3.51 (t, 2H, J=4.6).

[0209] General Method 10: Reduction of a nitrobenzene derivative to ananiline with zinc/calcium chloride dihydrate. To a solution of thenitrobenzene derivative (1.0 equiv) in ethanol:water (95:5) was addedzinc dust (4.30 equiv) and calcium chloride dihydrate (2.15 equiv) atroom temperature, whereupon the mixture was then heated to reflux. Colorchange of the solution from yellow to colorless indicated that thereaction was complete, with a reaction time of approximately 4-5 hours.The reaction mixture was filtered hot through a pad of celite and washedwith hot EtOAc (100 mL). The solvent was removed under reduced pressureand partitioned with water (150 mL) and EtOAc (150 mL). The aqueouslayer was then adjusted to a pH of 3-4 with 20% HCl, extracted withEtOAc (3×100 mL), washed with brine (100 mL), dried (MgSO₄) andconcentrated under reduced pressure. Purification by flashchromatography (silica gel, 20:1, CH₂Cl₂:MeOH) gave the desired product.

[0210] 7-Amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine(Structure 5 of Scheme I, where R⁶=H, R^(x)=4-anisyl). This compound wasprepared by General Method 10 from3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine (1.0 g, 3.3mmol) and purified by flash chromatography (CH₂Cl₂MeOH, 20:1) to afford900 mg (99%) of7-amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine. Data for7-amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine: R_(f) 0.60(24:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, 2H, J=8.6), 6.86(d, 2H, J=8.6), 6.60 (d, 1H, J=8.4), 6.34 (d, 1H, J=2.5), 6.30 (dd, 1H,J=8.5, 2.4), 4.25 (s, 2H), 4.21 (t, 2H, J=4.5), 3.80 (s, 3H), 3.17 (t,2H, J=4.3).

[0211](±)-1,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 120, Structure 10 of Scheme II, where R¹=H,R²=trifluoromethyl). This compound was prepared by General Method 5(EXAMPLE 1) from7-amino-3,4-dihydro-4-(p-methoxybenzyl)-2H-1,4-benzoxazine (1.78 g, 6.58mmol) and ethyl 4,4,4,-trifluoroacetoacetate (1.15 mL, 7.9 mmol), andpurified by flash chromatography (19:1 CH₂Cl₂:MeOH) to afford 533 mg(30%) of Compound 120. Data Compound 120: R_(f) 0.17 (3:2EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 10.73 (br s, 1H), 6.94 (s,1H), 6.87 (s, 1H), 6.75 (s, 1H), 4.35 (t, 2H, J=4.4), 3.99 (br s, 1H),3.50-3.42 (m, 1H).

EXAMPLE 201-Cyclopropylmethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinotin-7-one(Compound 121, Structure 11 of Scheme II, where R¹=H,R²=Trifluoromethyl, R^(x)=Cyclopropyl)

[0212] This compound was prepared by General Method 3 (EXAMPLE 1) fromCompound 120 (EXAMPLE 19) (55 mg, 0.21 mmol), cyclopropanecarboxaldehyde(100 mg, 1.5 mmol) and NaBH₃CN (65 mg, 1.01 mmol) to afford 64 mg (98%)of Compound 121. Data for Compound 121: R_(f) 0.29 (19:1 CH₂Cl₂:MeOH);¹H NMR (500 MHz, CDCl₃) δ 11.04 (br s, 1H), 7.00 (s, 1H), 6.88 (s, 1H),6.78 (s, 1H), 4.36 (t, 2H, J=4.4), 3.46 (t, 2H), J=4.4), 3.19 (d, 2H,J=6.3), 1.05 (m, 1H), 0.62-0.58 (m, 2H), 0.27 (m, 2H).

EXAMPLE 21

[0213]1,2,3,6-Tetrahydro-1-(2-pyridylmethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 122, Structure 11 of Scheme II, where R¹=H, R¹=trifluoromethylR^(x)=2-pyridyl). This compound was prepared by General Method 3(EXAMPLE 1) Compound 120 (EXAMPLE 19) (19 mg, 0.07 mmol),2-pyridinecarboxaldehyde (75.6 mg, 0.7 mmol) and NaBH₃CN (22 mg, 0.3mmol) to afford 9 mg (36%) of Compound 122. Data for Compound 122: R_(f)0.17 (19:1 CH₂Cl₂:MeOH); ¹H NMR (500MHz, CDCl₃) δ 11.48 (br s, 1 H),8.61 (d, 1H, J=5.5), 7.64 (t, 1H, J=6.9), 7.29 (d, 1H, J=7.8), 7.19 (dd,1H, J=7.2, 5.5), 6.84 (s, 1H), 6.82 (s, 2H), 4.60 (s, 2H), 4.42 (t, 2H,J=4.4), 3.60 (t, 2H, J=4.5).

EXAMPLE 22(±)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 123, Structure 18 of Scheme III, where R²=CF₃,R^(x)=Trifluoromethyl, R¹, R⁶, R⁷=H)

[0214] (2-Methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine. Thiscompound was prepared according to General Method 7 (EXAMPLE 5) from2-amino-5-nitroanisole (5.38 g, 32.0 mmol), trifluoroacetaldehydehydrate (26.5 mL, 37.1 g, 0.320 mol), NaBH₃CN (10.0 g, 0.160 mol) in 107mL trifluoroacetic acid to afford 7.6 g (95%) of(2-methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine, a light browncrystalline solid, after recrystallization (1:1 EtOAc:hexanes, 30 mL).Data for (2-methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine: R_(f)0.52 (2:1 hexanes:EtOAc); ¹H NMR (400 MHz, acetone-d₆) δ 7.87 (dd, 1H,J=8.9, 2.4), 7.69 (d, 1H, J=2.4), 6.96 (d, 1H, J=8.9), 6.38 (broad s,1H), 4.20 (qd, 2H, J=9.3, 7.1), 4.00 (s, 3H).

[0215] (4-Amino-2-methoxyphenyl)-2,2,2-(trifluoroethyl)amine (Structure13 of Scheme III, where R^(x)=CF₃). This compound was prepared accordingto General Method 10 (EXAMPLE 19) from(2-methoxy-4-nitrophenyl)-2,2,2-(trifluoroethyl)amine (8.40 g, 33.6mmol), zinc dust (9.66 g, 0.148 mmol), and calcium chloride dihydrate(10.9 g, 73.9 mmol) in 300 mL 95% EtOH/water to afford to 6.7 g (90%) of(4-amino-2-methoxyphenyl)-2,2,2-(trifluoroethyl)amine, a deep purpleoil. Data for (4-amino-2-methoxyphenyl)-2,2,2-(trifluoroethyl)amine:R_(f) 0.25 (1:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 6.54 (d, 1H,J=8.1), 6.20-6.30 (m, 2H), 4.15 (broad s, 1H), 3.81 (s, 3H), 3.68 (qd,2H, J=9.0, 7.4), 3.38 (broad s, 2H).

7-Methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-one(Structure 14 of Scheme III, where R¹=H, R²=Trifluoromethyl,R^(x)=Trifluoromethyl)

[0216] General Method 11: Condensation of an aniline with anacetoacetate derivative in benzene or toluene followed by a Knorrreaction in sulfuric acid. A solution of an aniline (1.0 equiv) inbenzene or toluene (10 mL/mmol) and an acetoacetate derivative (1.2equiv) was heated at reflux for 12-16 hrs. The resulting mixture wascooled to room temperature and concentrated under reduced pressure. Thecrude reaction mixture was diluted in concentrated sulfuric acid (8mL/mmol) and heated to 100° C. for 6-16 hrs. The resulting mixture waspoured over ice and neutralized with 6M NaOH solution to pH 7.0,extracted with CH₂Cl₂ (3×30 mL/mmol), washed with pH 7 phosphate buffer(50 mL/mmol) and brine (50 mL/mmol). The organic solution was dried(MgSO₄) and concentrated under reduced pressure. Purification wasperformed either by flash chromatography (silica gel, 20:1, CH₂Cl₂/MeOH)or by another specified method to afford the desired quinolone as afluorescent-yellow solid.

7-Methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-one(Structure 14 of Scheme III, where R¹=H, R²=Trifluoromethyl,R^(x)=Trifluoromethyl)

[0217] This compound was prepared according to General Method 11 from(5.72 g, 26.0 mmol) and ethyl 4,4,4-trifluoroacetoacetate (4.56 mL, 5.74g, 31.2 mmol) in 87 mL toluene, followed by treatment with 65 mLconcentrated H₂SO₄ to afford 2.72 g (30.7%) of7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-one,a fluffy yellow solid, after rinsing the crude material with a 1:1mixture of EtOAc:hexanes (60 mL). Data for7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-one:R_(f)0.19 (4:1 EtOAc:CH₂Cl₂); ¹H NMR (400 MHz, acetone-d₆) δ 10.87(broad s, 1H), 7.04 (s, 1H), 6.99 (broad s, 1H), 6.73 (s, 1H), 5.54(broad m, 1H), 4.07 (app quint, 2H, J=8.4), 3.98 (s, 3H).

[0218] General Method 12: Transformation of a pyridone to an isopropylimino ether with isopropyl iodide and cesium fluoride. To a suspensionof pyridone (1 equiv) and CsF (4 equiv) in DMF (0.25 M) was added2-iodopropane (4 equiv). The suspension was stirred for 18h, whereuponit was poured into cold water (25 mL/mmol) and extracted with EtOAc(2×25 mL/mmol). The organic layers were washed sequentially with water(2×15 mL/mmol) and brine (15 mL/mmol), dried over MgSO₄, filtered, andconcentrated to afford a yellow brown solid, which was used withoutfurther purification.

[0219]2-Isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline:This compound was prepared by General Method 12 from7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-trifluoromethyl-1H-quinolin-2-one(2.42 g, 7.11 mmol), CsF (4.32 g, 28.5 mmol), and 2-iodopropane (2.84mL, 4.84 g, 28.5 mmol) in 28 mL DMF to afford 2.47 g (90.6%) of2-isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline,a yellow brown solid, which was used without further purification. Datafor2-isopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline:R_(f) 0.24 (9:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.18 (s, 1H),7.02 (s, 1H), 7.01 (broad s, 1H), 5.48 (heptet, 1H, J=6.3), 4.87 (broadt, 1H, J=6.7), 4.02 (s, 3H), 3.88 (app quint, 2H, J=8.8), 1.39 (d, 6H,J=6.3).

[0220]7-Hydroxy-2-isopropyloxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline(Structure 15 of Scheme III, where R¹=H, R²=trifluoromethyl,R^(x)=trifluoromethyl): To a suspension of sodium hydride (60% mineraloil dispersion, 1.72 g, 6.13 mmol) in 20.6 mL DMF was added thiophenol(4.53 mL, 4.86 g, 44.1 mmol) at 0° C. After the bubbling subsided, asolution ofisopropyloxy-7-methoxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline(2.34 g, 6.13 mmol) in 10 mL DMF was added and the mixture was heated to110° C. After 5 h, the mixture was poured into cold water andneutralized with 21 mL 2 M NaHSO₄, and the aqueous layer was extractedwith ethyl acetate (2×200 mL). The organic layers were washedsequentially with water (2×100 mL) and brine (100 mL), dried over MgSO₄,filtered and concentrated. Flash chromatography (hexanes:EtOAc, 2:1)afforded 1.71 g (75.8%) of2-isopropyloxy-7-hydroxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline,a yellow solid. Data for7-hydroxy-2-isopropyloxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline:R_(f) 0.21 (4:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.18 (s, 1H),7.05 (broad s, 1H), 7.01 (s, 1H), 6.0 (v broad s, 1H), 5.42 (hept, 1H,J=6.1), 4.69 (broad t, 1H, J=6.9), 3.88 (m, 2H), 1.37 (d, 6H, J=6.1).

[0221] General Method 13: Cyclization of an o-bromoester onto ano-aminophenol to form a compound of Structure 16. To a suspension of anaminophenol of Structure 15 (1 equiv) and K₂CO₃ (2.05 equiv) in DMF(0.25 M) was added the α-bromoester (1.05 equiv). The mixture was heatedto 80° C. for 1 h, then heated to 110° C. for 4 h, then the reaction waspartitioned between EtOAc (50 mL/mmol), water (25 mL/mmol) and sat'dNH₄Cl (25 mL/mmol). The aqueous layer was extracted with EtOAc (25mL/mmol), and the combined organic layers were washed sequentially withwater (2×25 mL/mmol), brine (25 mL/mmol), dried over MgSO₄, filtered andconcentrated. This material was used without purification, or waspurified as indicated.

[0222]7-Isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(Structure 16 of Scheme III, where R²=CF₃, R^(x)=trifluoromethyl, R¹,R⁶, R⁷=H): This compound was prepared by General Method 13 from2-isopropyloxy-7-hydroxy-6-[(2,2,2-trifluoroethyl)amino]-4-(trifluoromethyl)quinoline(1.51 g, 4.10 mmol), K₂CO₃ (1.16 g, 8.40 mmol) and ethyl bromoacetate(0.719 g, 4.30 mmol) in 16.4 mL DMF to afford 1.57 g (94%) of7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one,a light yellow-brown solid, R_(f) 0.50 (4:1 hexanes:EtOAc); ¹H NMR (400MHz, CDCl₃) δ 7.57 (broad s, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 5.53(hept, 1H, J=6.2), 4.79 (s, 2H), 4.71 (q, 2H, J=8.4), 1.41 (d, 6H).

[0223] General Method 14: Methenylation of a tertiary amide of Structure16 and subsequent reduction with NaBH₃CN. To a solution of a substituted7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-onederivative (1 equiv) in THF (0.15 M) was added Tebbe reagent (0.5 M intoluene, 1.1 equiv) at 0° C. After 1 h, ether (50 mL/mmol) and methanol(0.7 mL/mmol) were added sequentially, and the brown solution wasallowed to warm to rt. After 30 min the mixture was filtered throughCelite, rinsed with ether, and concentrated to a deep orange-brownsolid. The solid was passed quickly through a plug of silica gel orbasic alumina to afford an orange solid which was carried on directly.To a suspension of the above solid and NaBH₃CN (5 equiv) indichloroethane (0.2 M) was added acetic acid (2.5 mL/mmol) dropwise at0° C. The mixture bubbled vigorously, and was allowed to warm to rt.After 1 d the orange solution was poured into NaHCO₃ (40 mL/mmol) andextracted with EtOAc (2×40 mL/mmol). The organic layers were washed withbrine (30 mL/mmol), dried over MgSO₄, filtered, and concentrated. Thematerial was purified as indicated.

[0224](±)-2,3-Dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 17 of Scheme III, where R²=CF₃, R^(x)=trifluoromethyl, R¹,R⁶, R⁷=H). This compound was made from General Method 14 from7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(0.689 g, 1.69 mmol), Tebbe's reagent (3.7 mL, 1.9 mmol) in 11 mL THF toafford 0.728 g of(±)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,an orange solid after filtration through silica gel. ¹H NMR (400 MHz,CDCl₃) δ 7.64 (broad s, 1H), 7.49 (s, 1H), 7.29 (s, 1H), 5.59 (hept, 1H,J=6.2), 4.95 (s, 2H), 4.91 (q, 2H, J=9.1), 1.58 (d, 6H, J=6.2).Subsequent treatment of the above solid (0.728 g) as described inGeneral Method 14 with NaBH₃CN (0.531 g, 8.45 mmol) and 4.2 mL aceticacid in 8.4 mL dichloroethane afforded 0.366 g (53%) of(±)-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow solid, after flash chromatography (hexanes:EtOAc, 9:1).R_(f)0.28 (9:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H),7.12 (s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.26 (dd, ABX, 1H,J=10.7, 2.4), 4.16 (dd, ABX, 1H, J=10.7, 2.8), 3.97-4.07 (m, 1H),3.77-3.87 (m, 1H), 3.61-3.68 (m, 1H), 1.38 (d, 6H, J=6.2). GeneralMethod 15: Hydrolysis of an isopropyl imino ether to a pyridone. Asolution of the imino ether in a 3:1 acetic acid:concentrated HCl(0.1-0.2 M) solution was heated at 60-110° C. for 4-16 h. The solutionwas poured into sat'd NaHCO₃ (80 mL/mmol), extracted with EtOAc (2×80mL/mmol), washed with brine (60 mL/mmol), dried over MgSO₄, filtered,concentrated, and purified as indicated.

[0225](±)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 123, Structure 18 of Scheme III, where R¹, R⁶, R⁷=H, R²=CF₃,R^(x)=tifluoromethyl). This compound was prepared according to GeneralMethod 15 from(±)-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(0.362 g, 0.887 mmol) in 1.6 mL conc. HCl and 4.8 mL acetic acid heatedto 110° C. for 5 h. The product was isolated by purification by flashchromatography (92:8 CH₂Cl₂:MeOH), followed by recrystallization frommethanol to afford 0.164 g (50%) of Compound 123, a yellow solid. Datafor Compound 123: HPLC (ODS, 7:3 MeOH:water, 3.0 mL/min) t_(R) 13.56min; ¹H NMR (400 MHz, CDCl₃) 11.07 (broad s, 1H), 7.08 (broad s, 1H),6.96 (s, 1H), 6.75 (s, 1H), 4.25-4.30 (m, 2H), 4.05-4.25 (m, 2H),3.72-3.82 (m, 1H), 1.28 (d, 3H, J=6.6); ¹³C (100 MHz, DMSO-d₆) 160.0,147.7, 135.6 (q, J=30.4), 134.3 (m), 129.9, 125.8 (q, J=282), 122.7 (q,J=275), 118.4 (broad s), 108.1, 106.0, 102.8, 68.8, 51.7, 50.9 (q,J=32.2), 15.0.

EXAMPLE 23

[0226](±)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 124, Structure (+)-18 of Scheme III, where R¹, R⁶, R⁷=H,R²=CF₃, R^(x)=trifluoromethyl), and(−)-1,2,3,6-Tetraydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 125, Structure (−)-18 of Scheme III, where R¹, R⁶, R⁷=H,R²=CF₃, R^(x)=trifluoromethyl). This compound was prepared according toGeneral Method 9 (EXAMPLE 15) from Compound 123 (EXAMPLE 22) (10 mg,0.03 mmol) on a semiprep Chitalpak AD column (20×250 mm) elutedhexanes/isopropanol (93:7), to afford 3.3 mg of Compound 124, a yellowsolid, and 3.0 mg of Compound 125, a yellow solid. Data for Compound124: HPLC (Chiralpak AD, 93:7 hexanes:isopropanol, 5.0 mL/min) t_(R)35.4 min; [α]_(D)=+39.3.

[0227] Data for Compound 125: HPLC (Chiralpak AD, 93:7hexanes:isopropanol, 5.0 mL/min) t_(R) 40.9, min; [α]_(D)=−41.3.

EXAMPLE 24(±)-trans-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 126, Structure 18 of Scheme III, where R¹=H, R²=CF₃, R⁶=H,R⁷=Me, R^(x)=Trifluoromethyl)

[0228]7-Isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(Structure 16 of Scheme III, where R¹=H, R²=CF₃, R⁶=H, R⁷=Me,R^(x)=trifluoromethyl). This compound was prepared according to GeneralMethod 13 (EXAMPLE 22) from2-isopropyloxy-7-hydroxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline(EXAMPLE 22) (55 mg, 0.15 mmol), ethyl 2-bromopropionate (29 mg, 0.16mmol) and K₂CO₃ (46 mg, 0.33 mmol) in 1.5 mL DMF to afford 61 mg (96%)of7-isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one.Data for7-isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one:R_(f)0.31 (9:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.55 (broad s,1H), 7.48 (s, 1H), 7.11 (s, 1H), 5.53 (hept, 1H, J=6.2), 4.81 (q, 2H,J=6.8), 4.60-4.76 (m, 2H), 1.64 (d, 3H, J=6.8), 1.41 (d, 6H, J=6.2).

[0229](±)-trans-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 17 of Scheme III, where R¹=H, R²=CF₃, R⁶=H, R⁷=Me,R^(x)=trifluoromethyl) and(±)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 17 of Scheme III, where R¹=H, R²=CF₃, R⁶=Me, R⁷=H,R^(x)=trifluoromethyl). This compound was prepared according to GeneralMethod 14 (EXAMPLE 22) from7-isopropoxy-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(19 mg, 0.046 mmol), Tebbe reagent (0.10 mL, 0.050 mmol) in 0.5 mL THFfollowed by reduction with NaBH₃CN (17 mg, 0.27 mmol) in 0.23 mL HOAcand 0.46 mL dichloroethane to afford 15 mg (78%) of a 3:1 mixture ofdiastereomers after flash chromatography (4:1 hexanes:EtOAc). Thediastereomers were separated on a Beckman HPLC (ODS Ultraspheresemi-prep column, 5 μm, 10×250 mm, 3.0 mL/min, 80% MeOH/water) to afford3.5 mg (18%) of(±)-trans-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow solid, and 6.5 mg (34%) of(±)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline.Data for(±)-trans-(±)-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:HPLC (ODS, 10×250 mm, 80% MeOH/water, 3 mL/min) t_(R) 50 min; R_(f)0.54(4:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 7.09 (broads, 1H), 6.98 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.40 (qd, 1H, J=6.5, 2.2),3.96-4.09 (m, 1H), 3.72-3.85 (m, 1H), 3.42 (qd, J=6.5, 2.0, 1H),1.35-1.42 (m, 9H), 1.14 (d, 3H, J=6.5).

[0230] Data for(±)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:HPLC (ODS, 10×250 mm, 80% MeOH/water, 3 mL/min) t_(R) 57 min; R_(f)0.51(4:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H), 7.09 (broads, 1H), 6.99 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.33 (qd, 1H, J=6.5, 1.8),4.03-4.16 (m, 1H), 3.72-3.84 (m, 1H), 3.36 (qd, J=6.7, 1.5), 1.38 (d,6H, J=6.2), 1.36 (d, 3H, J=6.5), 1.27 (d, 3H, J=6.6).

[0231](±)-trans-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 126, Structure 18 of Scheme III, where R¹=H, R²=CF₃, R⁶=H,R⁷=Me, R^(x)=trifluoromethyl). This compound was prepared according toGeneral Method 15 (EXAMPLE 22) from(±)-trans-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(3.5 mg, 0.0083 mmol) in 0.2 mL conc. HCl and 0.5 mL acetic acid heatedto 110° C. for 3 h, affording 2.5 mg (78%) of Compound 126 after flashchromatography (92:8 CH₂Cl₂:MeOH). Data for Compound 126: R_(f)0.20(92:8 CH₂Cl₂:MeOH): ¹H NMR (400 MHz, CDCl₃) δ 11.50 (broad s, 1H), 7.01(broad s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 4.32 (qd, 1H, J=6.3, 1.9),3.93-4.08 (m, 1H), 3.67-3.82 (m, 1H), 3.32 (qd, 1H, J=6.5, 1.3), 1.34(d, 3H, J=6.4), 1.23 (d, 3H, J=6.5).

EXAMPLE 25(±)-cis-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 127, Structure 18 of Scheme III, where R¹=H, R²=CF₃, R⁶=Me,R⁷=H, R^(x)=Trifluoromethyl)

[0232] This compound was prepared according to General Method 15(EXAMPLE 22) from(±)-cis-2,3-dihydro-7-isopropoxy-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(EXAMPLE 24) (6.0 mg, 0.014 mmol) in 0.2 mL conc. HCl and 0.5 mL aceticacid heated to 110° C. for 3 h, affording 4.5 mg (85%) of Compound 127after flash chromatography (92:8 CH₂Cl₂:MeOH). Data for Compound 127:R_(f)0.20 (92:8, CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 12.06 (broad s,1H), 7.02 (broad s, 1H), 6.92 (s, 1H), 6.90 (s, 1H), 4.37 (qd, 1H,J=6.4, 1.8), 3.83-3.98 (m, 1H), 3.68-3.82 (m, 1H), 3.38 (qd, 1H,J=6.7,1.6), 1.37 (d, 3H, J=6.4), 1.11 (d, 3H, J=6.6).

EXAMPLE 26(±)-trans-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 128, Structure 18 of Scheme III, where R¹=H, R²=CF₃, R⁶=H,R⁷=Et, R^(x)=Trifluoromethyl)

[0233](±)-3-Ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(Structure 16 of Scheme III, where R¹=H, R²=CF₃, R⁶=H, R⁷=Et,R^(x)=trifluoromethyl). This compound was prepared according to GeneralMethod 13 (EXAMPLE 22) from2-isopropyloxy-7-hydroxy-6-[2,2,2-(trifluoroethyl)amino]-4-(trifluoromethyl)quinoline(EXAMPLE 22) (70 mg, 0.19 mmol), ethyl 2-bromobutanoate (41 mg, 0.21mmol) and K₂CO₃ (58 mg, 0.42 mmol) in 1.9 mL DMF to afford 63 mg (76%)of(±)-3-ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one.Data for(±)-3-ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one:R_(f)0.47 (5.7:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) 7.54 (broad s,1H), 7.49 (s, 1H), 7.11 (s, 1 H), 5.53 (hept, 1H, J=6.2), 4.72-4.83 (m,1 H), 4.66 (dd, 1H, J=8.5, 4.8), 4.55-4.65 (m, 1 H), 1.85-2.10 (m, 2 H),1.41 (d, 6H, J=6.2), 1.11 (t, 3H, J=7.4).

[0234](±)-trans-3-Ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 17 of Scheme III, where R¹=H, R²=CF₃, R⁶=H, R⁷=Et,R^(x)=trifluoromethyl) and(±)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 17 of Scheme III, where R¹=H, R²=CF₃, R⁶=Et, R⁷=H,R^(x)=trifluoromethyl). This compound was prepared according to GeneralMethod 14 (EXAMPLE 22) from3-ethyl-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(39 mg, 0.089 mmol), Tebbe reagent (0.20 mL, 0.098 mmol) in 0.9 mL THFfollowed by reduction with NaBH₃CN (34 mg, 0.53 mmol) in 0.45 m HOAc and0.90 mL dichloroethane to afford 9 mg (23%) of(±)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow solid, and 7 mg of a 1:1 mixture of diastereomers after flashchromatography (9:1 hexanes:EtOAc). The diastereomers were separated ona Beckman HPLC (ODS Ultrasphere semi-prep column, 5 μm, 10×250 mm, 3.0mL/min, 90% MeOH/water) to afford 3 mg (8%) of(±)-trans-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow solid. Data for(±)-trans-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:HPLC (ODS, 10×250 mm, 90% MeOH/water, 3 mL/min) t_(R) 16.2 min;R_(f)0.25 (9:1 hexanes:EtOAc); ¹H NMR (400 MHz, benzene-d₆) δ 7.70 (s,1H), 7.28 (broad s, 1H), 7.02 (s, 1H), 5.55 (hept, 1H, J=6.2), 3.41-3.52(m, 2H), 2.90-3.01 (m, 1H), 2.63 (broad q, 1H, J=6.3), 1.48-1.57 (m,1H), 1.30 (d, 3H, J=6.5), 1.28 (d, 3H, J=6.5), 1.11-1.20 (m, 1H), 0.78(t, 3H, J=7.5), 0.76 (d, 3H, J=6.5).

[0235] Data for(±)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:HPLC (ODS, 10×250 mm, 90% MeOH/water, 3 mL/min) t_(R) 19.4 min;R_(f)0.28 (9:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H),7.09 (s, 1H), 6.98 (s, 1H), 5.47 (hept, 1H, J=6.2), 4.09 (ddd, 1H,J=7.9, 5.5, 2.0), 3.96-4.06 (m, 1H), 3.74-3.84 (m, 1H), 3.47 (qd, 1H,J=6.5, 2.0), 1.65-1.88 (m, 1H), 1.50-1.62 (m, 1H), 1.37 (d, 6H, J=6.2),1.12 (d, 3H, J=6.6), 1.10 (t, 3H, J=7.4).

[0236](±)-trans-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 128, Structure 18 of Scheme III, where R¹=H, R²=CF₃, R⁶=H,R⁷=Et, R^(x)=trifluoromethyl).

[0237] This compound was prepared according to General Method 15 from(±)-trans-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(3 mg, 0.007 mmol) in 0.1 mL conc. HCl and 1.5 mL acetic acid heated at100° C. for 18 h to afford 1.7 mg (63%) of Compound 128, a yellow solid.Data for Compound 128: ¹H NMR (400 MHz, CDCl₃) δ 11.83 (broad s, 1H),6.99 (broad s, 1H), 6.91 (s, 2H), 3.92-4.05 (m, 2H), 3.68-3.79 (m, 1H),3.41 (qd, 1H, J=6.7, 1.4), 1.66-1.75 (m, 1H), 1.53-1.62 (m, 1H), 1.24(d, 3H, J=6.6), 1.01 (t, 3H, J=7.5).

EXAMPLE 27(±)-cis-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 129, Structure 18 of Scheme III, where R¹=H, R²=CF₃, R⁶=Et,R⁷=H, R^(x)=Trifluoromethyl)

[0238] This compound was prepared according to General Method 15(EXAMPLE 22) from(±)-cis-3-ethyl-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(EXAMPLE 26) (8 mg, 0.018 mmol) in 0.1 mL conc. HCl and 1.5 mL aceticacid heated at 100° C. for 18 h to afford 5 mg (71%) of Compound 129, ayellow solid. Data for Compound 129: R_(f)0.19 (19:1 CH₂Cl₂:MeOH); ¹HNMR (400 MHz, CDCl₃) δ 12.48 (broad s, 1H), 7.02 (broad s, 1H), 6.97 (s,1H), 6.93 (s, 1H), 4.04-4.10 (m, 1H), 3.86-3.97 (m, 1H), 3.69-3.80 (m,1H), 3.42 (dq, 1H, J=6.5, 1.9), 1.73-1.83 (m, 1H), 1.50-1.60 (m, 1H),1.07-1.11 (m, 6H).

EXAMPLE 28(±)-1,2,3,6-Tetrahydro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 130, Structure 20 Scheme IV, where R¹, R⁶, R⁷=H,R²=Trifluoromethyl)

[0239](±)-2,3-Dihydro-2-(hydroxymethyl)-7-isopronoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 19 of Scheme IV, where R¹, R⁶, R⁷=H, R²=trifluoromethyl): Toa solution of7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(EXAMPLE 22) (0.183 g, 0.448 mmol) in 4.8 mL THF was added Tebbe reagent(0.99 mL, 0.49 mmol) at 0° C. After 1 h, ether (22 mL) and MeOH (0.32mL) were added sequentially and the mixture was allowed to warm to rt.The slurry was filtered through Celite and concentrated, and theresultant residues was filtered through a short plug of basic alumina(4:1 hexanes:EtOAc) to afford 0.20 g of(±)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline.This residue was dissolved in 2.2 mL THF, and BH₃ THF solution (1M, 0.49mL, 0.49 mmol) was added dropwise at 0° C. After 15 min, the mixture wasallowed to warm to rt, whereupon 0.1 mL MeOH was added and the solutionallowed to stir for 16 h. The solvent was removed in vacuo, and theresidue was redissolved in 2.2 mL THF and 0.45 mL MeOH, whereupon 0.10mL 6N NaOH and a 35% H₂O₂ solution (0.055 mL, 60.9 mg, 0.63 mmol) wasadded. A precipitate was formed which was filtered with 20 mL THF. Thefiltrate was concentrated, and the resultant solid was dissolved in 1 mLMeOH, acidified with 0.05 mL conc. HCl, and the solution concentrated invacuo. The residue was treated with 0.1 mL 6N NaOH, and partitionedbetween water (20 mL) and EtOAc (20 mL). The aqueous layer was extractedwith EtOAc (2×20 mL), and the combined organic layers were washed withbrine (20 mL), dried over MgSO₄, filtered, and concentrated. Flashchromatography (2:1 hexanes:EtOAc) afforded 91 mg (48%) of(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a light amber oil. Data for(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:R_(f)0.34 (2:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.30 (s, 1H),7.17 (broad s, 1H), 7.01 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.50 (dd, 1H,J=11.1, 1.6), 4.12-4.25 (m, 1H), 3.96-4.09 (m, 1H), 3.78-3.90 (m, 2H),3.61-3.67 (m, 1H), 1.71 (t, 1H, J=5.1), 1.38 (d, 6H, J=6.2).

[0240](±)-1,2,3,6-Tetrahydro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 130, Structure 20 of Scheme IV, where R¹, R⁶, R⁷=H,R²=trifluoromethyl). A solution of(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(20 mg, 0.047 mmol) in 1.0 mL conc. HCl was heated at 90° C. for 4 h,whereupon the solution was poured into cold sat'd NaHCO₃ (20 mL) andextracted with EtOAc (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried over MgSO₄, filtered, and concentrated. Flashchromatography (2:1 hexanes:EtOAc) afforded 12 mg (67%) of Compound 130,a yellow solid. Data for Compound 130: R_(f)0.21 (3:2 EtOAc: CH₂Cl₂); ¹HNMR (400 MHz, acetone-d₆) δ 10.95 (broad s, 1H), 7.10 (broad s, 1H),6.95 (s, 1H), 6.74 (s, 1H), 4.58 (dd, 1H, J=10.9, 1.5), 4.20-4.42 (m.3H), 4.17 (dd, 1H, J=10.9, 2.2), 3.72-3.81 (m, 1H), 3.59-3.73 (m, 2H).

EXAMPLE 29

[0241](±)-1,2,3,6-Tetrahydro-2-(acetoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 131, Structure 21 of Scheme IV, where R¹, R⁶, R⁷=H,R²=trifluoromethyl). This compound was prepared by General Method 15(EXAMPLE 22) from(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(EXAMPLE 28) (4.6 mg, 0.011 mmol) in 0.1 mL conc. HCl and 0.5 mL HOAcheated at 100° C. for 3 h to afford 1.6 mg (35%) of Compound 131, ayellow solid. Data for Compound 131: R_(f)0.21 (3:2 EtOAc:CH₂Cl₂); ¹HNMR (400 MHz, CDCl₃) δ 11.25 (broad s, 1H), 7.10 (broad s, 1H), 6.93 (s,1H), 6.89 (s, 1H), 4.44 (dd, 1H, J=11.0, 1.3), 4.26 (dd, 1H, ABX,J=11.3, 6.0), 4.15 (dd, 1H, J=11.0, 2.5), 4.10 (dd, ABX, J=11.4, 7.9),4.02-4.14 (m, 1H), 3.84-3.96 (m, 1H), 3.68-3.74 (m, 1H), 2.09 (s, 3H).

EXAMPLE 30(±)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 132, Structure 23 of Scheme IV, where R¹, R⁶, R⁷=H,R²=Trifluoromethyl, R⁵=Me)

[0242] General Method 16: Alkylation of an alcohol of Structure 19 tocompound of Structure 22 with an alkyl halide. To a solution of acompound of Structure 19 (1 equiv) and sodium hydride (60% mineral oildispersion, 4 equiv) in THF (0.03-0.04 M) was added the specified alkylhalide (4 equiv). After TLC analysis show the consumption of startingmaterial (6-18 h), the reaction mixture was quenched with 1 M phosphatebuffer (500 mL/mmol), extracted with EtOAc (2×500 mL/mmol). The organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated, and purified as indicated.

[0243](±)-2,3-Dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 22 of Scheme IV where R¹, R⁶, R⁷=H, R²=trifluoromethyl,R⁵=Me). This compound was prepared by General Method 16 from(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(EXAMPLE 28) (10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) andiodomethane (17 mg, 0.12 mmol) in 0.6 mL THF to afford 8.3 mg (81%) of(±)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow solid, after flash chromatography (5:1 hexanes:EtOAc). Data for(±)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:R_(f)0.21 (3:1 hexanes: EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H),7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.43 (dd, 1H,J=11.0, 1.6), 4.16 (dd, J=11.0, 2.6), 3.98-4.21 (m, 2 H), 3.67-3.73 (m,1H), 3.50-3.60 (m, 2 H), 3.37 (s, 3 H), 1.38 (d, 6H, J=6.2).

[0244](±)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 132, Structure 23 of Scheme IV, where R¹, R⁶, R⁷=H,R²=trifluoromethyl, R⁵=Me). This compound was prepared according toGeneral Method 15 (EXAMPLE 22) from(±)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(8.3 mg, 0.019 mmol) in 0.1 mL conc. HCl and 0.5 mL acetic acid heatedat 100° C. for 4.5 h to afford 6.0 mg (80%) of Compound 132, a yellowsolid. Data for Compound 132: R_(f)0.48 (2:1 EtOAc:CH₂Cl₂); ¹H NMR (400MHz, CDCl₃) δ 12.09 (broad s, 1H), 7.06 (broad s, 1H), 6.94 (s, 1H),6.92 (s, 1H), 4.43 (dd, 1H, J=10.9, 1.2), 4.14 (dd, J=10.9, 2.3),3.93-4.12 (m, 2H), 3.63-3.70 (m, 1 H), 3.44-3.56 (m, 2H), 3.36 (s, 3H).

EXAMPLE 31

[0245](±)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 133, Structure (±)-23 of Scheme IV, where R¹, R⁶, R⁷=H,R²=trifluoromethyl, R⁵=Me) and(−)-1,2,3,6-tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-2]quinolin-7-one(Compound 134, Structure (−)-23 of Scheme IV, R¹, where R¹, R⁶, R⁷=H,R²=trifluoromethyl, R⁵=Me). This compound was prepared according toGeneral Method 9 (EXAMPLE 15) from Compound 132 (5 mg, 0.013 mmol) on asemiprep Chiralpak AD column (20×250 mm), hexanes/isopropanol (95:5), toafford 1.8 mg of Compound 133, a yellow solid, and 1.8 mg of Compound134, a yellow solid. Data for Compound 133: HPLC (Chiralpak AD, 95:5hexanes:isopropanol, 5.0 mL/min) t_(R) 35.7 min; [α]_(D)=+40.0.

[0246] Data for Compound 134: HPLC (Chiralpak AD, 93:7hexanes:isopropanol, 5.0 mL/min) t_(R) 40.9 min; [α]_(D)=−43.8.

EXAMPLE 32(±)-2-(Ethoxymethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 135, Structure 23 of Scheme IV, where R¹, RR⁶, R⁷=H,R²=Trifluoromethyl, R⁵=Et)

[0247](±)-2-(Ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 22 of Scheme IV, where R¹, R⁶, R⁷=H, R²=trifluoromethyl,R⁵=Et). This compound was prepared according to General Method 16(EXAMPLE 30) from(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(EXAMPLE 28) (10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) and iodoethane(17 mg, 0.12 mmol) in 1.0 mL THF to afford 9.8 mg (89%) of(±)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow oil, after flash chromatography (5:1 hexanes:EtOAc). Data for(±)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:R_(f)0.60 (5:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H),7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.45 (dd, 1H,J=10.9, 1.5), 4.16 (dd, J=10.9, 2.5), 4.00-4.20 (m, 2H), 3.70 (broad t,1H, J=6.8), 3.54-3.63 (m, 2H), 3.50 (q, 2H, J=6.9), 1.38 (d, 6H, J=6.2),1.20 (t, 3H, J=7.0).

(±)-2-(Ethoxymethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 135, Structure 23 of Scheme IV, where R¹, R⁶, R⁷=H,R²=Trifluoromethyl, R⁵=Et)

[0248] This compound was prepared according to General Method 15(EXAMPLE 22) from2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(9.8 mg, 0.022 mmol) in 0.1 mL conc. HCl and 0.5 mL acetic acid heatedat 100° C. for 4 h to afford 6.0 mg (67%) of Compound 135, a yellowsolid. Data for Compound 135: R_(f)0.25 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR(400 MHz, CDCl₃) δ 12.3 (broad s, 1H), 7.06 (broad s, 1H), 6.95 (s, 1H),6.92 (s, 1H), 4.44 (broad d, 1H, J=11.0), 4.14, (dd, 1H, J=10.9, 2.2),3.95-4.10 (m, 2H), 3.67 (broad t, 1H, J=6.9), 3.45-3.60 (m, 4H), 1.19(t, 3H, J=7.0).

EXAMPLE 33(±)-1,2,3,6-Tetrahydro-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 136, Structure 23 of Scheme IV, where R¹, R⁶, R⁷=H,R²=Trifluoromethyl, R⁵=n-Pr)(±)-2,3-Dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 22 of Scheme IV, where R¹, R⁶, R⁷=H, R²=Trifluoromethyl,R⁵=n-Pr)

[0249] This compound was prepared according to General Method 16(EXAMPLE 30) from(±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(EXAMPLE 28) (11 mg, 0.026 mmol), NaH (5.0 mg, 0.12 mmol) and1-iodopropane (21 mg, 0.12 mmol) in 1.0 mL THF to afford 6 mg (50%) of(±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,a yellow oil, after flash chromatography (5:1 hexanes:EtOAc). Data for(±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:R_(f)0.57 (5:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.28 (s, 1H),7.13 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.44 (dd, 1H,J=10.9, 1.8), 4.17 (dd, 1H, J=11.0, 2.5), 4.00-4.20 (m, 2H), 3.71 (broadt, 1H, J=6.8), 3.54-3.64 (m, 2H), 3.40 (broad t, 2H, J=6.6), 1.52-1.62(m, 2H), 1.38 (d, 6H, J=6.2), 0.91 (t, 3H, J=7.4).

[0250](±)-1,2,3,6-Tetrahydro-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 136, Structure 23 of Scheme IV, where R¹, R⁶, R⁷=H,R²=trifluoromethyl, R⁵=n-Pr). This compound was prepared according toGeneral Method 15 (EXAMPLE 22) from(±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(6.0 mg, 0.013 mmol) in 0.1 mL conc. HCl and 0.5 mL acetic acid heatedat 100° C. for 4 h to afford 3.1 mg (56%) of Compound 136, a yellowsolid. Data for Compound 136: R_(f)0.25 (11.5:1 CH₂Cl₂:MeOH); ¹H NMR(400 MHz, CDCl₃) δ 11.75 (broad s, 1H), 7.06 (broad s, 1H), 6.92 (s,1H), 6.90 (s, 1H), 4.44 (dd, 1H, J=10.9, 1.7), 4.14 (dd, 1H, J=10.9,2.5), 3.94-4.08 (m, 2H), 3.65-3.70 (m, 1H), 3.47-3.59 (m, 2H), 3.39 (t,2H, J=6.6), 1.50-1.62 (m, 2 H), 0.91 (t, 3H, J=7.4).

EXAMPLE 34

[0251]1,6-Dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3,2-g]-quinolin-2,7-dione(Compound 137, Structure 24 of Scheme V, where R¹, R⁶, R⁷=H,R²=trifluoromethyl). This Compound was prepared according to GeneralMethod 15 (EXAMPLE 22) from7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(EXAMPLE 22) (72 mg, 0.18 mmol), in 0.5 mL conc. HCl and 2.0 mL aceticacid heated at 60° C. for 16 h to afford 42 mg (65%) of Compound 137, anoff-white solid, after flash chromatography (92:8 CH₂Cl₂:MeOH). Data forCompound 137: R_(f)0.34 (92:8 CH₂Cl₂:MeOH); ¹H NMR (400 MHz, acetone-d₆)δ 11.11 (broad s, 1H), 7.52 (s, 1H), 7.18 (s, 1H), 6.86 (s, 1H), 4.95(q, 2H, J=9.0), 4.90 (s, 2H).

EXAMPLE 35

[0252](±)-1,2,3,6-Tetrahydro-2-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 138, Structure 25 of Scheme V, where, R¹, R⁶, R⁷=H, R⁴=Me,R²=trifluoromethyl). To a solution of Compound 137 (EXAMPLE 34) (0.012g, 0.033 mmol) in 1 mL THF and 0.1 mL HMPA and was added MeLi solution(1.4 M in ether, 0.12 mL, 0.16 mmol) at −78° C. for 0.5 h. The reactionwas quenched with 20 mL phosphate buffer (pH=7) and extracted with EtOAc(2×20 mL). The organic fractions were dried over Na₂SO₄, filtered, andconcentrated. Flash chromatography (5% methanol/CH₂Cl₂) gave 8 mg (62%yield) of Compound 138, a yellow solid. ¹H NMR (400MHz, acetone-d₆)10.92 (br s, 1H), 7.13 (br s, 1H), 6.96 (s, 1H), 6.75 (s, 1H), 4.34-4.24(m, 1H), 4.23 (d, 1H, J=11.6), 4.19 (d, 1H, J=10.8), 4.07-3.96 (m, 1H),1.49 (s, 3H).

EXAMPLE 36

[0253]1,6-Dihydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3,2-g]-quinolin-2,7-dione(Compound 139, Structure 24 of Scheme V, where R¹, R⁶=H,R²=trifluoromethyl, R⁷=Me): A mixture of7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(EXAMPLE 22) (7.0 mg, 0.017 mmol) in 0.5 mL 57% HI was heated to 65° C.for 16 h, whereupon it was poured onto cold NaHCO₃ (25 mL). The mixturewas extracted with EtOAc (25 mL), and the organic layer was washedsequentially with 1 M phosphate buffer (10 mL) and brine (10 mL), driedover MgSO₄, filtered, and concentrated. Flash chromatography (92:8CH₂Cl₂:MeOH) afforded 1.4 mg (22%) of Compound 139, an off-white solid.Data for Compound 139: R_(f)0.37 (92:8 CH₂Cl₂:MeOH; ¹H NMR (400 MHz,acetone-d₆) δ 11.09 (broad s, 1H), 7.52 (s, 1H), 7.19 (s, 1H), 6.86 (s,1H), 4.80-5.05 (m, 3H), 1.59 (d, 3H, J=6.7).

EXAMPLE 371,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-2-thioxo-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 140, Structure 27 of Scheme V, where R¹, R⁶, R⁷=H,R²=Trifluoromethyl)

[0254]7-Isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-thione(Structure 26 of Scheme V, where R¹, R⁶, R⁷=H, R²=trifluoromethyl). Amixture of7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one(EXAMPLE 22) (48.4 mg, 0.119 mmol) and Lawesson's reagent (0.144 g,0.356 mmol) in 2.4 mL toluene was heated at reflux for 6 h, whereuponthe mixture was partitioned between EtOAc (40 mL) and water (20 mL). Theaqueous layer was extracted with EtOAc (20 mL), and the combined organiclayers were washed with brine (20 mL), dried over MgSO4, filtered, andconcentrated. Flash chromatography (9:1 hexanes:EtOAc) afforded 41 mg of7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-thione,a yellow oil. Data for7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-thione:R_(f)0.36 (9:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.72 (broad s,1H), 7.48 (s, 1H), 7.13 (s, 1H), 5.54 (hept, 1H, J=6.2), 5.32-5.42 (m,2H), 5.05 (s, 2H), 1.41 (d, 6H, J=6.2).

[0255]1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-2-thioxo-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 140, Structure 27 of Scheme V, where R¹, R⁶, R⁷=H,R²=trifluoromethyl). To a solution of7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-thione(30 mg, 0.071 mmol) in 1.4 mL CH₂Cl₂ was added BCl₃ (1 M in CH₂Cl₂, 1.2mL, 1.2 mmol). After 8 h, the mixture was quenched with saturated NaHCO₃(15 mL) and extracted with EtOAc (2×15 mL). The organic layers werewashed with brine (15 mL), dried over MgSO₄, filtered, and concentrated.Flash chromatography (3:2 CH₂Cl₂:EtOAc) afforded 17 mg (63%) of Compound140, an off-white solid. Data for Compound 140: R_(f)0.36 (3:2CH₂Cl₂:EtOAc); ¹H NMR (400 MHz, acetone-d₆) δ 11.22 (broad s, 1H), 7.72(broad s, 1H), 7.19 (s, 1H), 6.90 (s, 1H), 5.62-5.75 (m, 2H), 5.16 (s,2H).

EXAMPLE 38(±)-1,2,3,6-Tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 141, Structure 30 of Scheme VI where R⁴=Me).

[0256] (2-Methoxy-4-nitrophenyl)-(4-methoxybenzal)amine. This compoundwas prepared according to General Method 3 (EXAMPLE 1) from2-amino-5-nitroanisole (1.00 g, 5.95 mmol), p-anisaldehyde (1.62 g, 11.9mmol), NaBH₃CN (0.373 g, 5.95 mmol) in 100 mL acetic acid to afford 1.25g (75%) of (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine, an orangesolid, after washing the crude product with 4:1 hexanes:EtOAc. Data for(2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine: R_(f)0.80 (3:2EtOAc:hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.88 (dd, 1H, J=8.8, 2.4),7.64 (d, 1H, J=2.4), 7.22-7.28 (m, 2H), 6.85-6.90 (m, 2H), 6.51 (d, 1H,J=9.0), 5.31 (broad s, 1H), 4.38 (d, 2H, J=5.4), 3.93 (s, 3H), 3.82 (s,3H).

[0257] (4-Amino-2-methoxyphenyl)-(4-methoxybenzyl)amine (Structure 13 ofScheme III, where R^(x)=4-anisyl). This compound was prepared by GeneralMethod 10 (EXAMPLE 19) from(2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine (1.92 g, 6.65 mmol),zinc dust (1.87 g, 28.6 mmol), and calcium chloride dihydrate (2.10 g,14.3 mmol) in 350 mL 95:5 EtOH:water to afford 1.23 g (70%) of(4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine, a light purple solid,after flash chromatography (CH₂Cl₂:MeOH 19:1). Data for(4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine: R_(f)0.80 (19:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, 2H, J=8.6), 6.87 (d,2H, J=8.6), 6.47 (d, 1H, J=8.1), 6.28 (d, 1H, J=2.4), 6.23 (dd, 1H,J=8.1, 2.4), 4.20 (s, 2H), 4.10 (v broad s, 1H), 3.80 (s, 3H), 3.79 (s,3H), 3.31 (broad s, 2H).

[0258] 6-Amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one. Thiscompound was prepared according to General Method 11 (EXAMPLE 22) from(4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine (1.23 g, 4.76 mmol) andethyl 4,4,4-trifluoroacetoacetate (1.05 g, 5.71 mmol) in 60 mL benzenefollowed by treatment with 10 mL concentrated H₂SO₄ to afford 0.734(60%) of 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one, ayellow solid, after rinsing with MeOH:ether:hexanes. Data for6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one: R_(f)0.28 (19:1CH₂Cl₂:MeOH); ¹H NMR (500 MHz, CDCl₃) δ 12.2 (v broad s, 1H), 7.06(broad s, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 4.01 (s, 3H), 3.94 (broad s,2H).

[0259] 6-Amino-2-isopropoxy-7-methoxy-4-(trifluoromethyl)quinoline. Thiscompound was prepared according to General Method 12 (EXAMPLE 22) from6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one (500 mg, 1.9mmol), CsF (1.18 g, 7.7 mmol), isopropyl iodide (1.31 g, 7.7 mmol) in 8mL DMF to afford 308 mg (53%) of6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline, a lightyellow oil, and 190 mg (29%) of2-isopropyloxy-7-methoxy-6N-(isopropyl)amino-4-(trifluoromethyl)quinoline,after flash chromatography (7:3 hexanes:EtOAc). Data for6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline: R_(f)0.51(4:1 hexanes:EtOAc); ¹H NMR (500 MHz, CDCl₃) δ 7.18 (s, 1H), 7.13 (broads, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.3), 4.11 (broad s, 2H), 4.01(s, 3H), 1.40 (d, 6H, J=6.3).

[0260] 6-Amino-7-hydroxy-2-isopropyloxy-4-(trifluoromethyl)quinoline(Structure 28 of Scheme VI). To a suspension of sodium hydride (60%mineral oil dispersion, 180 mg, 4.6 mmol, rinsed with hexanes) in 3.5 mLDMF was added thiophenol (550 mg, 5.0 mmol) at 0° C., whereupon asolution of6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline (200 mg,0.67 mmol) in 2 mL DMF was added. The mixture was heated at 110° C. for6 h, then poured into ice, and the pH was adjusted to 5 by the additionof 2N NaHSO₄. The mixture was extracted with EtOAc (2×30 mL), washedsequentially with water (30 mL) and brine (30 mL), dried over Na₂SO₄,filtered, and concentrated. Flash chromatography (4:1 hexanes:EtOAc)afforded 147 mg (77%) of6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline, a tansolid. Data for6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline: R_(f)0.14(4:1 hexanes:EtOAc); ¹H NMR (500 MHz, CDCl₃) δ 7.19 (broad s, 1H), 7.16(s, 1H), 6.99 (s, 1H), 5.60 (v. broad s, 1H), 5.45 (hept, 1H, J=6.2),4.00 (v. broad s, 2H), 1.38 (d, 6H, J=6.3).

[0261] General Method 17. Alkylation of an α-halo-ketone to ano-aminophenol and subsequent reductive cyclization to a 1,4-oxazinederivative. To a solution of 2-amino-5-nitrophenol (1.0 equiv) inacetone (0.6 mL/mmol) was added an α-halo ketone (1.1 equiv) and K₂CO₃(1.1 equiv) at 0° C. under N₂. The reaction mixture was allowed to warmto room temperature and stirred for 6-8 hours. The crude reactionmixture was then evaporated under reduced pressure and washed with water(3×100 mL) and the resulting solid was dried under high vacuum. To thiscrude solid (1.0 equiv) in trifluoroacetic acid (0.26 M) was addedportionwise NaBH₃CN (1.0 equiv) and stirred at room temperature under N₂overnight. The resulting mixture was poured over ice and neutralizedwith 6M NaOH to pH 7.0, extracted with EtOAc (3×30 mL/mmol), washed withbrine (50 mL/mmol). The organic solution was dried (MgSO₄) andconcentrated under reduced pressure. Purification by flashchromatography (silica gel, 19:1, CH₂Cl₂/MeOH) afforded the desired1,4-oxazine derivative.

[0262](±)-2,3-Dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 29 of Scheme VI, where R⁴=Me). This compound was prepared byGeneral Method 17 from6-amino-3,4-dihydro-7-hydroxy-2-isopropoxy-4-(trifluoromethyl)quinoline(15 mg, 0.05 mmol), chloroacetone (5.0 μL, 0.06 mmol), and K₂CO₃ (8.0mg, 0.06 mmol) to afford 13 mg of crude solid. The crude solid (13 mg,0.04 mmol), NaBH₃CN (2.5 mg, 0.04 mmol) and trifluoroacetic acidafforded 10.0 mg (77%) of(±)-2,3-dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline.Data for(±)-2,3-dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:R_(f)0.84 (2:3, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.24 (s, 1H),7.02 (d, 1H, J=2.0), 6.97 (s, 1H), 5.48 (m, 1H), 4.30 (dd, 1H, J=10.6,2.7), 4.12 (br s, 1H), 3.88 (dd, 1H, J=10.7, 8.3), 3.64 (m, 1H), 1.38(d, 6H, J=6.3), 1.24 (d, 3H, J=6.8).

[0263](±)-1,2,3,6-Tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 141, Structure 30 of Scheme VI, where R⁴=Me). This compoundwas prepared by General Method 15 (EXAMPLE 22) from(±)-2,3-dihydro-7-isopropoxy-2-methyl-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(10.0 mg, 0.03 mmol) in 0.2 mL HCl and 1 mL HOAc heated at 80° C. for 6h to afford 7.0 mg (77%) of Compound 141, a yellow solid, afterpurification by flash chromatography (3:2, EtOAc/hexanes). Data forCompound 141: R_(f)0.31 (3:2, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ12.14 (br s, 1H), 6.94 (s, 1H), 6.89 (s, 2H), 4.29 (dd, 1H, J=8.3, 2.0),3.94 (br s, 1H), 3.86 (dd, 1H, J=10.5, 8.5), 3.58 (m, 1H), 1.23 (d, 3H,J=6.3).

EXAMPLE 39

[0264](±)-1-Cyclopropylmethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 142, Structure 31 of Scheme VI, where R⁴=Me,R^(x)=cyclopropyl). This compound was prepared by General Method 3(EXAMPLE 1) from Compound 141 (7.0 mg, 0.02 mmol), cyclopropanecarboxaldehyde (17.3 mg, 0.2 mmol) and NaBH₃CN (7.7 mg, 0.1 mmol) toafford 6.6 mg (82%) of Compound 142. Data for Compound 142: R_(f)0.36(3:2, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 11.58 (br s, 1H), 6.98(s, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 4.26 (dd, 1H, J=10.7, 2.4), 4.14(dd, 1H, J=10.5, 2.7), 3.72 (m, 1H), 3.32 (dd, 1H, J=14.6, 5.8), 3.02(dd, 1H, J=14.6, 4.3), 1.22 (d, 3H, J=6.3), 1.05 (m, 1H), 0.63 (m, 2H),0.3 (m, 2H).

EXAMPLE 40(±)-2-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 143, Structure 30 of Scheme VI, where R⁴=Et)

[0265](±)-2-Ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(Structure 29 of Scheme VI, where R⁴=Et). This compound was prepared byGeneral Method 17 (EXAMPLE 38) from6-amino-7-hydroxy-2-isopropoxy-4-(trifluoromethyl)quinoline (EXAMPLE 36)(15 mg, 0.05 mmol), 1-bromo-2-butanone (6.0 μL, 0.06 mmol), and K₂CO₃(8.0 mg, 0.06 mmol) to afford 16 mg of crude solid. The crude solid (16mg, 0.05 mmol), NaBH₃CN (3.0 mg, 0.05 mmol) and trifluoroacetic acidafforded 13 mg (81%) of(±)-2-ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline.Data for(±)-2-ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline:R_(f)0.78 (2:3, EtOAc:hexanes) ¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H),7.01 (s, 1H), 6.96 (s, 1H), 5.47 (m, 1H), 4.33 (dd, 1H, J=10.6, 2.5),4.20 (br s, 1H), 3.95 (dd, 1H, J=10.6, 7.9), 3.40 (m, 1H), 1.58 (m, 2H),1.37 (d, 6H, J=6.1), 1.06 (t, 3H, J=7.5).

[0266](±)-2-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 143, Structure 30 of Scheme VI, where R⁴=Et). This compoundwas prepared by General Method 15 (EXAMPLE 22) from(±)-2-ethyl-2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline(13.0 mg, 0.04 mmol) and was purified by flash chromatography (3:2,EtOAc/hexanes) to yield 8.1 mg (72%) of Compound 143. Data Compound 143:R_(f)0.34 (3:2, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 12.11 (br s,1H), 6.95 (s, 1H), 6.89 (s, 1H), 6.88 (s, 1H), 4.34 (dd, 1H, J=10.2,2.5), 4.02 (br s, 1H), 3.93 (dd, 1H, J=10.7, 7.8), 3.35 (m, 1H), 1.56(m, 2H), 1.06 (t, 3H, J=7.5).

EXAMPLE 41

[0267](±)-1-(Cyclopropylmethyl)-2-ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 144, Structure 31 of Scheme VI, where R⁴=Et,R^(x)=cyclopropyl). This compound was prepared by General Method 3(EXAMPLE 1) from Compound 143 (8.1 mg, 0.03 mmol), cyclopropanecarboxaldehyde (19.1 mg, 0.2 mmol) and NaBH₃CN (8.5 mg, 0.1 mmol) andpurified by HPLC (75:25 MeOH:water, semi-prep ODS column @ 3 mL/min) toafford 4.0 mg (44%) of Compound 144. Data for Compound 144: R_(f)0.30(3:2, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 11.72 (br s, 1H), 6.96(s, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 4.34 (dd, 1H, J=10.7, 1.9), 4.15(dd, 1H, J=10.7, 2.4), 3.39 (m, 2H), 3.0 (m, 1H), 1.59 (m, 2H), 1.06 (m,1H), 0.98 (t, 3H, J=7.8), 0.62 (m, 2H), 0.29 (m, 2H).

EXAMPLE 41A1,2,3,6-Tetrahydro-1-isopropyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 144A, Structure 31D of Scheme VIA, where R¹=R⁴=R⁶=H,R²=Trifluoromethyl, R¹³=isopropyl)

[0268]2-Isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline(Structure 31B of Scheme VIA, where R¹=H, R²=trifluoromethyl,R¹³=isopropyl, R^(A)=isopropyloxy). A suspension of6-amino-7-methoxy-4-trifluoromethyl-1H-quinolin-2-one (0.50 g, 1.9mmol), CsF (1.18 g, 7.7 mmol) and isopropyl iodide (1.31 g (7.7 mmol) in8 mL DMF was stirred at 30° C. for 18 h, whereupon the mixture wasquenched with pH 7 phosphate buffer and extracted with EtOAc (2×). Thecombined organic layers were washed sequentially with water (2×) andbrine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (7:3, hexanes:EtOAc) afforded 0.19 g (32%) of2-isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline,an oil. Data for Compound2-isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline:¹H NMR (400 MHz, CDCl₃) δ 7.13 (s, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 5.47(sept, 1H, J=6.2), 4.37 (d, 1H, J=7.4), 3.99 (s, 3H), 3.70-3.80 (m, 1H),1.39 (d, 6H, J=6.2), 1.30 (d, 6H, J=6.2).

[0269]2-Isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline(Structure 31C of Scheme VIA, where R¹=H, R²=trifluoromethyl,R¹³=isopropyl, R^(A)=isopropyloxy). A solution of2-isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline(0.10 g, 0.30 mmol), thiophenol (0.24 g, 2.2 mmol), and NaH (60%dispersion in mineral oil, 78 mg, 2.0 mmol) in 2 mL DMF was heated at110° C. for 5 h, whereupon the mixture was poured over ice, and adjustedto pH 5 with 2M NaHSO₄. The aqueous layer was extracted with EtOAc (2×),and the combined organic layers were washed sequentially with water (2×)and brine, dried over MgSO₄, filtered and concentrated. Flashchromatography (4:1 hexanes:EtOAc) afforded 90 mg (95%) of2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline,a yellow oil. Data for2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline:¹H NMR (400 MHz, CDCl₃) δ 7.16 (s, 1H), 6.98 (s, 1H), 6.92 (s, 1H), 5.37(sept, 1H, J=6.2), 3.70 (sept, 1H, J=6.3), 1.35 (d, 6H, J=6.2), 1.29 (d,6H, J=6.3).

[0270]1,2,3,6-Tetrahydro-1-isopropyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 144A, Structure 31D of Scheme VIA, where R¹=R⁴=R⁶=H,R²=trifluoromethyl, R¹³=isopropyl). A suspension of2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline(60 mg, 0.18 mmol), 1,2-dibromoethane (62 mg, 0.33 mmol) and K₂CO₃ (47mg, 0.34 mmol) in 3 mL acetone and 1.5 mL water was heated at reflux for18 h, whereupon the mixture was partitioned between water and EtOAc. Theaqueous layer was extracted with EtOAc, and the combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated.Flash chromatography (4:1 hexanes:EtOAc) afforded 27 mg of a yellow oilwhich was carried on directly by treatment with 0.05 mL concentrated HCland 0.5 mL HOAc and heated at 70° C. for 4 h, whereupon the reaction waspoured over ice and adjusted to pH 7 with 25% aqueous NaOH. The aqueouslayer was extracted with EtOAc (3×), and the combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated.Flash chromatography (3:2 hexanes:EtOAc) afforded 10 mg (30%) ofCompound 144A, a yellow solid. Data for Compound 144A: ¹H NMR (500 MHz,CDCl₃) δ 12.0 (broad s, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 6.80 (s, 1H),4.34 (t, 2H, J=4.6, 2H), 4.08 (sept, 1H, J=6.3), 3.26 (t, 2H, J=4.6),1.22 (d, 6H, J=6.3).

EXAMPLE 42(±)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 145, Structure 35 of Scheme VII, where R¹=H, R²=CF₃, R⁴=Et,R^(x)=Trifluoromethyl)

[0271] (±)-3-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (Structure 32of Scheme VII, where R⁴=Et). This compound was prepared by GeneralMethod 17 (EXAMPLE 38) from 2-amino-5-nitrophenol (2.0 g, 13.0 mmol),1-bromo-2-butanone (1.45 mL, 14.2 mmol), and K₂CO₃ (1.97 g, 14.2 mmol)to afford 3.0 g of crude solid. The crude solid (3.0 g, 13.3 mmol),NaBH₃CN (837 mg, 13.3 mmol) and trifluoroacetic acid afforded 1.96 g(70%) (±)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine afterpurification by flash chromatography (19:1, CH₂Cl₂/MeOH). Data for(±)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: R_(f)0.57 (2:3EtOAc:hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.74 (dd, 1H, J=8.7, 2.6),7.69 (d, 1H, J=2.6), 6.51 (d, 1H, J=8.8), 4.59 (br s, 1H), 4.25 (dd, 1H,J=10.7, 3.2), 3.86 (dd, 1H, J=10.7, 7.1), 3.43 (m, 1H), 1.6 (m, 2H),1.05 (t, 3H, J=7.4).

[0272](±)-3-Ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 33 of Scheme VII, where R⁴=Et, R^(x)=CF₃). This compound wasprepared by General Method 7 (EXAMPLE 5) from(±)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (200 mg, 0.96 mmol),2,2,2-trifluoroacetaldehyde monohydrate (1.12 g, 9.6 mmol) and NaBH₃CN(292 mg, 4.6 mmol) to afford 100 mg (36%) of3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,a yellow solid. Data for(±)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.69 (2:3 EtOAc:hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.80 (dd, 1H,J=8.9, 2.6), 7.71 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.0), 4.34 (dd, 1H,J=10.9, 1.4), 4.19-4.05 (m, 1H), 4.02 (dd, 1H, J=11.0, 2.3), 3.87-3.72(m, 1H), 1.72-1.62 (m, 2H), 1.00 (t, 3H, J=7.4).

[0273](±)-7-Amino-3-ethyl-3,4-dihydro-4-[2,2,2(trifluoroethyl)]-2H-1,4-benzoxazine(Structure 34 of Scheme VII, where R⁴=Et, R^(x)=CF₃). This compound wasprepared by General Method 4 (EXAMPLE 1) from(±)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(100 mg, 0.34 mmol) and purified by flash chromatography (EtOAc:hexanes,3:2) to afford 83 mg (93%) of(±)-7-amino-3-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine.Data for(±)-7-amino-3-ethyl-3,4-dihydro-4-[2,2,2(trifluoroethyl)]-2H-1,4-benzoxazine:R_(f)0.63 (3:2 EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.64 (d, 1H,J=8.3), 6.28 (dd, 1H, J=8.5, 2.7), 6.23 (d, 1H, J=2.4), 4.15 (d, 1H,J=10.7), 3.96 (dd, 1H, J=10.7, 2.4), 3.65 (m, 1H), 3.40 (br, s, 1H),3.03 (m, 1H), 1.53 (m, 2H), 0.96 (t, 3H, J=7.6).

[0274](±)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 145, Structure 35 of Scheme VII, where R¹=H, R²=CF₃, R⁴=Et,R^(x)=trifluoromethyl). This compound was prepared by General Method 5(EXAMPLE 1) from(±)-7-amino-3-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(83 mg, 0.32 mmol) and ethyl 4,4,4-trifluoroacetoacetate (70 mg, 0.38mmol) and purified by flash chromatography (3:2 EtOAc:hexanes) to yield54 mg (44%) of Compound 145. Data for Compound 145: R_(f)0.36 (3:2EtOAc:hexanes); ¹H NMR (500 MHz, CDCl₃) δ 11.67 (br s, 1 h), 7.07 (s,1H), 6.91 (s, 1H), 6.89 (s, 1H), 4.35 (dd, 1H, J=10.7, 2.0), 4.15 (dd,1H, J=10.7, 2.4), 4.04-3.97 (m, 1H), 3.75 (m, 1H), 3.28 (m, 1H), 1.64(m, 2H), 1.00 (t, 3H, J=7.3).

EXAMPLE 43(±)-1,2-Diethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 146, Structure 35 of Scheme VII, where R¹=H, R²=CF₃, R⁴=Et,R^(x)=CH₃)

[0275] (±)-3,4-Diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (Structure33 of Scheme VII, where R⁴=Et, R^(x)=CH₃). This compound was prepared byGeneral Method 3 (EXAMPLE 1) from3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 42) (200 mg,0.96 mmol), acetaldehyde (424 mg, 9.6 mmol) and NaBH₃CN (293 mg, 4.6mmol) to afford 170 mg (75%) of(±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid.Data for (±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine:R_(f)0.80 (3:2 EtOAc:hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.80 (dd, 1H,J=8.9, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.07 (dd, ABX,1H, J=10.7, 2.5), 3.96 (dd, ABX, 1H, J=10.7, 2.6), 3.60 (m, 1H),3.55-3.35 (m, 2H), 1.29 (d, 3H, J=6.6), 1.24 (t, 3H, J=7.0).

[0276] (±)-7-Amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine (Structure34 of Scheme VII, where R⁴=Et, R^(x)=CH₃). This compound was prepared byGeneral Method 4 (EXAMPLE 1) from(±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (170 mg, 0.72mmol) and purified by flash chromatography (EtOAc:hexanes, 3:2) toafford 39 mg (25%) of(±)-7-amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine. Data for(±)-7-amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine: (3:2EtOAc:hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.57 (d, 1H, J=8.3), 6.26-6.20(m, 2H), 4.12 (dd, ABX, 1H, J=10.3, 2.4), 3.92 (dd, ABX, 1H, J=10.7,2.4), 3.32-3.28 (m, 3H), 3.15-3.10 (m, 1H), 3.01 (m, 1H), 1.57-1.48 (m,2H), 1.15 (t, 3H, J=7.0), 0.94 (t, 3H, J=7.3).

[0277](±)-1,2-Diethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 146, Structure 35 of Scheme VII, where R¹=H, R²=CF₃, R⁴=Et,R^(x)=CH₃). This compound was prepared by General Method 5 (EXAMPLE 1)from (±)-7-amino-3,4-diethyl-3,4-dihydro-2H-1,4-benzoxazine (39 mg, 0.18mmol) and ethyl 4,4,4-trifluoroacetoacetate (42 mg, 0.22 mmol) andpurified by flash chromatography (19:1, CH₂Cl₂/MeOH) to yield 15 mg(25%) of Compound 146. Data for Compound 146: R_(f)0.28 (19:1,CH₂Cl₂:MeOH); ¹H NMR (500 MHz, CDCl₃) δ 11.50 (br s, 1H), 6.89 (s, 1H),6.88 (s, 1H), 6.84 (s, 1H), 4.32 (dd, ABX, 1H, J=10.7, 2.0), 4.06 (dd,ABX, 1H, J=10.7, 2.7), 3.51-3.47 (m, 1H), 3.30-3.23 (m, 2H), 1.66-1.60(m, 2H), 1.25 (t, 3H, J=7.3), 0.98 (t, 3H, J=7.3).

EXAMPLE 43A(±)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 146A, Structure 35 of Scheme VII, where R¹=H, R²,R⁴=Trifluoromethyl, R^(x)=CF₃)

[0278] 2-(Trifluoroethyl)amino-5-nitrophenol (Structure 32A of SchemeVIIA, where R^(x)=CF₃). This compound was prepared by General Method 7(EXAMPLE 5) from 2-amino-5-nitrophenol (5.0 g, 32 mmol),2,2,2-trifluoroacetaldehyde ethyl hemiacetal (9.4 g, 65 mmol) andNaBH₃CN (4.1 g, 65 mmol) in 90 mL trifluoroacetic acid to afford 5.5 g(72%) of 2-(trifluoroethyl)amino-5-nitrophenol, a yellow solid, afterflash chromatography (3:1 hexanes:EtOAc). Data for2-(trifluoroethyl)amino-5-nitrophenol: ¹H NMR (400 MHz, acetone-d₆) 9.48(broad s, 1H), 7.79 (dd, 1H, J=9.1, 2.4), 7.67 (d, 1H, J=2.4), 6.96 (d,1H, J=8.8), 6.20 (broad s, 1H), 4.26-4.18 (m, 2H)

[0279](±)-3,4-Dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine(Structure 33 of Scheme VIIA, where R⁴=trifluoromethyl, R^(x)=CF₃). Thiscompound was prepared by General Method 17 (EXAMPLE 38) from2-(trifluoroethyl)amino-5-nitrophenol (1.00 g, 4.23 mmol),3-bromo-1,1,1-trifluoroacetone (4.84 g, 25.4 mmol), and K₂CO₃ (2.34 g,16.9 mmol) to afford 1.5 g of crude solid. This was combined withanother lot of the same reaction (4.2 mmol) and purified by flashchromatography (1:1 hexanes:EtOAc) to afford 1.0 g (40%) of a yellowoil. This material (725 mg, 2.47 mmol) was treated with 20 mLtrifluoroacetic acid and NaBH₃CN (776 mg, 12.4 mmol) to afford 0.26 g(38%) (±)-3,4-dihydro-7-nitro-3-(trifluoromethyl)-2H-1,4-benzoxazineafter purification by flash chromatography (3:1 hexanes:EtOAc). Data for(±)-3,4-dihydro-7-nitro-3-(trifluoromethyl)-2H-1,4-benzoxazine: ¹H NMR(400 MHz, CDCl₃) 7.87 (dd, 1H, J=9.1, 2.8), 7.81 (d, 1H, J=2.5), 6.92(d, 1H, J=9.1), 4.73 (d, 1H, J=12.1), 4.48-4.39 (m, 1H), 4.13-4.06 (m,2H), 3.99-3.88 (m, 1H).

[0280](±)-7-Amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine(Structure 34 of Scheme VII, where R⁴=trifluoromethyl, R^(x)=CF₃). Thiscompound was prepared by General Method 4 (EXAMPLE 1) from(±)-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine(45 mg, 0.16 mmol) and 10% Pd—C (30 mg) and purified by flashchromatography (EtOAc:hexanes, 1:1) to afford 26 mg (65%) of(±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine.Data for(±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine:¹H NMR (400 MHz, CDCl₃) 6.68 (d, 1H, J=8.4), 6.32-6.28 (m, 2H), 4.56(dd, 1H, J=12.0, 0.96), 4.16-4.00 (m, 2H), 3.84-3.69 (m, 2H), 3.60-3.32(m, 2H).

[0281](±)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 146A. Structure 35 of Scheme VII, where R¹=H, R²,R⁴=trifluoromethyl, R^(x)=CF₃). This compound was prepared by GeneralMethod 11 (EXAMPLE 22) from(±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine(26 mg, 0.11 mmol) and ethyl 4,4,4-trifluoroacetoacetate (58 mg, 0.32mmol) in 1.5 mL toluene followed by treatment with 1 mL H₂SO₄ afforded35 mg (90%) of Compound 146A. Data for Compound 146A: ¹H NMR (400 MHz,CDCl₃) 12.6 (broad s, 1H), 7.19 (broad s, 1H), 7.04 (s, 1H), 6.96 (s,1H), 4.73 (d, 1H, J=11.7), 4.42-4.31 (m, 1H), 4.23-4.19 (m, 1H),4.02-3.95 (m, 1H), 3.96-3.84 (m, 1H).

EXAMPLE 43B(+)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 146B, Structure (+)-35 of Scheme VII, where R¹=H, R²,R⁴=Trifluoromethyl, R^(x)=CF₃) and(−)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[4,1]oxazino[3,2-g]quinolin-7-one(Compound 146C, Structure (−)-35 of Scheme VIIA, where R¹=H, R²,R⁴=Trifluoromethyl, R^(x)=CF₃)

[0282] This compound was prepared according to General Method 9 (EXAMPLE15) from Compound 146A (EXAMPLE 42A) (10 mg, 0.03 mmol) on a semiprepChiralpak AD column (20×250 mm) eluted hexanes/isopropanol (95:5), toafford 4.5 mg of Compound 146B, an orange solid, and 4.7 mg of Compound146C, an orange solid. Data for Compound 146B: HPLC (Chiralpak AD, 95:5hexanes:isopropanol, 5.0 mL/min) t_(R) 54.1 min; [α]_(D)=+62.7.

[0283] Data for Compound 146C: HPLC (Chiralpak AD, 95:5hexanes:isopropanol, 5.0 mL/min) t_(R) 64.3 min; [α]_(D)=−60.4.

EXAMPLE 44(±)-1-Ethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 147, Structure 35 of Scheme VII, where R¹=H,R²=Trifluoromethyl, R⁴=Me, R^(x)=CH₃)

[0284] (±)-3,4-Dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine (Structure 32of Scheme VII, where R⁴=Me). This compound was prepared by GeneralMethod 17 (EXAMPLE 38) from 2-amino-5-nitrophenol (4.0 g, 25.9 mmol),chloroacetone (2.27 mL, 28.5 mmol), and K₂CO₃ (3.94 g, 28.5 mmol) toafford 3.5 g of crude solid. The crude solid (3.0 g, 14.2 mmol), NaBH₃CN(892 mg, 14.2 mmol) and trifluoroacetic acid afforded 2.68 g (97%) of3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine. Data for(±)-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine: R_(f)0.51 (2:3,EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.74 (dd, 1H, J=8.7, 2.6),7.70 (d, 1H, J=2.3), 6.50 (d, 1H, J=8.7), 4.46 (br s, 1H), 4.23 (dd, 1H,J=10.5, 2.8), 3.76 (dd, 1H, J=10.5, 7.8), 3.67 (m, 1H), 1.25 (d, 3H,J=6.4).

[0285] (±)-4-Ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine(Structure 33 of Scheme VII, where R⁴=Me, R^(x)=CH₃). This compound wasprepared by General Method 3 (EXAMPLE 1) from(±)-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine (200 mg, 1.0 mmol),acetaldehyde (455 mg, 10.3 mmol) and NaBH₃CN (314 mg, 5.0 mmol) toafford 144 mg (63%) of4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine. Data for(±)-4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine: R_(f)0.80(3:2 EtOAc:hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.80 (dd, 1H, J=8.9, 2.6),7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.07 (dd, 1H, J=10.7, 2.5),3.96 (dd, 1H, J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d,3H, J=6.6), 1.24 (d, 3H, J=7.0).

[0286] (±)-7-Amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine(Structure 34 of Scheme VII, where R⁴=Me, R^(x)=CH₃). This compound wasprepared by General Method 4 (EXAMPLE 1) from(±)-4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine (140 mg,0.62 mmol) and purified by flash chromatography (EtOAc:hexanes, 3:2) toafford 90 mg (74%) of(±)-7-amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine. Data for(±)-7-amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine: R_(f)0.48(3:2 EtOAc:hexanes) ¹H NMR (400 MHz, CDCl₃) δ 6.53 (d, 1H, J=8.0),6.26-6.20 (m, 2H), 4.04 (dd, 1H, J=10.5, 2.6), 3.94 (dd, 1H, J=10.4,4.3), 3.37-3.26 (m, 4H), 3.17-3.07 (m, 11H), 1.13 (m, 6H).

[0287](±)-1-Ethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 147. Structure 35 of Scheme VII, where R¹=H,R²=trifluoromethyl, R⁴=Me, R^(x)=CH₃). This compound was prepared byGeneral Method 5 (EXAMPLE 1) from(±)-7-amino-4-ethyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine (90 mg, 0.47mmol) and ethyl 4,4,4-trifluoroacetoacetate (103 mg, 0.56 mmol) andpurified by flash chromatography (3:2 EtOAc:hexanes) to yield 46 mg(30%) of Compound 147. Data for Compound 147: R_(f)0.37 (3:2,EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 12.07 (br s, 1H), 6.89 (s,1H), 6.88 (s, 2H), 4.18 (dd, 1H, J=10.5, 2.5), 4.09 (dd, 1H, J=10.6,3.4), 3.54-3.51 (m, 1H), 3.47-3.40 (m, 1H), 3.31-3.24 (m 1H), 1.23 (m,6H)

EXAMPLE 45(2R-)-(−)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]-quinolin-7-onebenzoxazine (Compound 148, Structure 41 of Scheme VIII, where R¹=H,R²=Trifluoromethyl, R⁴=Me, R^(x)=CF₃)

[0288] General Method 18: Displacement of a halonitroaromatic compoundwith an amino alcohol. A mixture of the halonitrobenzene (1.2 equiv) andthe amino alcohol (1 equiv) was dissolved in absolute ethanol (3.3 M) orDMF. To this solution was added sodium bicarbonate (1 equiv). Thesuspension was heated at reflux temperature for 12 h when TLC indicatedcomplete conversion of the amino alcohol. After cooling to roomtemperature, the reaction mixture was filtered with the aid ofadditional ethanol and the filtrate was concentrated under reducedpressure, which was then purified as indicated.

[0289] (2R)-(+)-2-(2-Fluoro-4-nitrophenyl)amino-1-propanol (Structure 36of Scheme VIII, where R⁴=Me). This compound was prepared according toGeneral Method 18 from 3,4-difluoronitrobenzene (76.2 g 0.48 mol),R-(+)-2-amino-1-propanol (30 g, 0.40 mol) and sodium bicarbonate (33.6g, 0.40 mol) in 120 mL ethanol to afford 68.4 g (80%) of(2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-propanol, a yellow solid,after recrystallization from ethanol. Data for(2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-propanol: mp 128.2-129.7° C.;[α]_(D)=+22.6 (EtOH, c 3.1); ¹H NMR (400 MHz, CDCl₃) δ 7.99 (1H, dd,J=11.4), 7.89 (1H, dd, J=2.5, 11.6), 6.72 (1H, dd, J=8.7), 4.75 (1H,bs), 3.8 (2H, m), 3.69 (1H, m), 1.31 (3H, d,J=6.4).

[0290] General Method 19: Formation of an oxazolidine from anaminoalcohol and a carbonyl derivative, or its corresponding hydrate orhemiacetal. A r.b. flask equipped with a Dean-Stark condenser wascharged sequentially with the amino alcohol (1 equiv), benzene (0.3-0.5M), trifluoroacetaldehyde ethyl hemiacetal (5 equiv), andp-toluenesulfonic acid (catalytic). The reaction mixture was refluxedwith azeotropic removal of water for 10-12 h. After cooling to roomtemperature the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and washed withaqueous sodium bicarbonate, brine and dried over anhydrous MgSO₄. Afterfiltration, the solvents were removed under reduced pressure to affordthe desired oxazolidine. cis-(2S,4R)-(−)-3-(2-Fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidineandtrans-(2R,4R)-(+)-3-(2-Fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidine(Structure 37 of Scheme VIII where R⁴=Me, R^(x)=CF₃). These compoundswere prepared according to General Method 19 from(2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-propanol (68 g, 0.317 mole),750 mL of benzene, trifluoroacetaldehyde ethyl hemiacetal (229 g, 1.58mole), and 100 mg of p-toluenesulfonic acid (100 mg, 0.53 mmol) toaffordcis-(2S,4R)-(−)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidineandtrans-(2R,4R)-(+)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidineas a low melting solid. The product was found to be a mixture of twodiastereoisomers (cis/trans 4:1). Crystallization from ethylacetate-hexanes furnished the major (cis) isomer as pale yellow needlesand the minor (trans) isomer as a glassy solid. The combined yield ofboth compounds was 93.2 g (100%).

[0291] Data forcis-(2S,4R)-(−)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidine:mp 46-50° C.; [α]_(D)=−60.9 (CHCl₃, c 10.3); ¹H NMR (CDCl₃) δ 8.01 (1H,m), 7.98 (1H, dd, J=2.5, 12.3), 6.96 (1H, dd, J=9.0), 5.75 (1H, q,J=4.7), 4.33 (1H, m), 4.19 (1H, m), 3.99 (1H, m), 1.45 (3H, d, J=6.26).Data fortrans-(2R,4R)-(+)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidine:[α]_(D)=+258.9 (CHCl₃, c 8.25); ¹H NMR (CDCl₃) δ 8.02 (1H, dd), 7.98(1H, dd, J=2.5, 12.9). 6.96 (1H, dd, J=8.5), 5.83 (1H, q, J=4.7), 4.48(1H, m), 4.40 (1H, m), 3.95 (1H, m), 1.23 (3H, d, J=6.0).

[0292](2R)-(−)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol(Structure 38 of Scheme VIII, where R⁴=Me R^(x)=CF₃). A 1-L three-neckedRB flask equipped with an addition funnel and mechanical stirrer wascharged sequentially withcis-(2S,4R)-(−)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidineandtrans-(2R,4R)-(+)-3-(2-fluoro-4-nitrophenyl)-4-methyl-2-trifluoromethyloxazolidine(93 g, 0.36 mole), 600 mL of dry chloroform, and triethylsilane (183.7g, 1.58 mol). The solution was cooled to −78° C. and TiCl₄ (90 g, 0.474mol) was added dropwise via addition funnel. After the addition wascomplete, the reaction mixture was allowed to warm to room temperatureand stirred for another 24 h. The reaction mixture was quenched with iceand then neutralized with aqueous Na₂CO₃. The organic layers were washedwith water, brine and dried over MgSO₄. After filtration, the solventswere evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate: hexanes 1:9) to afford57 g (61%) of(2R)-(−)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol,as a glassy solid. Data for(2R)-(−)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol[α]_(D)=−205.9 (EtOH, c 10.15) ¹H NMR (CDCl₃) δ 7.99 (1H, dd, J=2.5,9.0), 7.95 (1H, dd, J=2.6, 14,7), 7.32 (1H, dd, J=8.6), 3.94 (1H, m),3.74 (2H, m), 3.65 (1H, m), 1.86 (1H, bs), 1.19 (3H, d, J=6.7).

[0293] General Method 20: Intramolecular cyclization of an alcohol ofStructure 38 or 42 on a haloaromatic to form a benzoxazine. A solutionof the aminoalcohol (1 equiv) in dry THF (1M) was added to a suspensionof NaH (1.5 equiv) in dry THF (2M) and the mixture was heated at reflux.After cooling, methanol (50 mL/mol) was added to consume excess sodiumhydride. The reaction mixture was poured into ice-cold water andextracted with ethyl acetate. The organic portions were combined, washedwith brine and dried over MgSO₄. After filtration, the solvents wereevaporated under reduced pressure and purified as indicated.

(3R)-(+)-3,4-Dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 39 of Scheme VIII, where R⁴=Me, R^(x)=CF₃)

[0294] This compound was prepared according to General Method 20 from(2R)-(−)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-propanol(57 g, 0.193 mol) in 200 mL and NaH (6.93 g, 0.289 mole) in 400 mL ofdry THF heated at reflux for 3 h to afford 36.5 g (68%) of(3R)-(+)-2,3-dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,a yellow crystalline solid, after flash chromatography. Data for(3R)-(+)-2,3-dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:mp 95.5-96.4° C.; [α]_(D)=+57.8 (EtOH, c 2.25); ¹H NMR (CDCl₃) δ 7.80(1H, dd, J=2.5, 9.1), 7.73 (1H, d, J=2.6), 6.71 (1H, d, J=9.1), 4.13(2H, m), 4.03 (1H, m), 3.84 (1H, m), 3.69 (1H, m), 1.31 (3H, dJ=6.6).

[0295](3R)-(−)-7-Amino-3,4-dihydro-3-methyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 40 of Scheme VIII, where R⁴=Me, R^(x)=CF₃). This compound wasprepared according to General Method 4 (EXAMPLE 1) from(3R)-(+)-2,3-dihydro-3-methyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(35.5 g, 0.128 mol) and 10% palladium on carbon (3 g) in 400 mL of ethylacetate to afford 31 g (98%) of(3R)-(−)-7-amino-2,3-dihydro-3-methyl-4-trifluoroethyl-2H-1,4-benzoxazine,an off-white solid, after purification by silica gel columnchromatography (ethyl acetate-hexanes). Data for(3R)-(−)-7-amino-2,3-dihydro-3-methyl-4-trifluoroethyl-2H-1,4-benzoxazine:[α]_(D)=−39.4 (EtOH, c 1.7) ¹H NMR (CDCl₃) δ 6.58 (1H, d, J=8.2), 6.40(1H, m), 6.37 (1H, m), 4.05 (1H, dd, J=2.3, 11.0), 3.98 (1H, dd, J=2.9,10.6), 3.66 (2H, m), 3.38 (1H, m), 3.40 (NH2), 1.18 (3H, d, J=6.6).

[0296](2R-)-(−)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-onebenzoxazine (Compound 148, Structure 41 of Scheme VIII, where R¹=H,R²=trifluoromethyl, R⁴=Me, R^(x)=CFI).

[0297] A mixture of(3R)-(−)-7-amino-3,4-dihydro-3-methyl-4-trifluoroethyl-2H-1,4-benzoxazine(4.14 g, 16.8 mmol) and of ethyl 4,4,4-trifluoroacetoacetate (4.64 g, 25mmol) were taken up in 85 mL of wet toluene (5% H₂O). The reactionmixture was refluxed for 24 h. After cooling to room temperature, thesolvents were evaporated under reduced pressure. The crude anilideobtained as a glassy solid was then treated with 50 mL of concentratedH₂SO₄. The reaction mixture was then slowly warmed to 70° C. and then to98° C. After 45 min, the heating bath was removed and the reactionmixture was allowed to cool to room temperature and then poured on tocrushed ice with vigorous stirring. The yellow precipitate formed wasfiltered, washed with distilled water, and dried under vacuum. The crudeproduct thus obtained was purified by silica gel column chromatography(ethyl acetate:hexanes), followed by recrystallization from ethylacetate-hexanes to afford 2.6 g (42.3%) of Compound 148, a bright-yellowcrystalline solid. Data for Compound 148: mp 219-223.1° C.;[α]_(D)=−81.7 (EtOH, c 2.4); ¹H NMR (CDCl₃) δ 7.05 (1H, s), 6.91 (1H,s), 6.89 (1H, s), 4.23 (1H, dd, J=2.4, 10.8), 4.14 (1H, dd, J=2.7,10.7), 3.92 (1H, m), 3.78 (H, m), 3.61 (1H, m) 1.27 (3H, d J=6.6).

EXAMPLE 46(2R-)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 149, Structure 41 of Scheme VIII, where R¹=H,R²=Trifluoromethyl, R⁴=Et, R^(x)=CF₃)

[0298] (2R)-2-(2-Fluoro-4-nitrophenyl)amino-1-butanol (Structure 36 ofScheme VIII, where R⁴=Et). This compound was prepared according toGeneral Method 18 (EXAMPLE 45) from 3,4-difluoronitrobenzene (5.34 mL,0.048 mol), R-(−)-2 amino-1-butanol (4.14 mL, 0.044 mol) and sodiumbicarbonate (3.68 g, 0.044 mol) in 133 mL anhydrous DMF heated at 90° C.for 12 hrs to afford 9.9 g (99%) of(2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol, a yellow oil, afterflash chromatography (gradient elution, hexanes:ethyl acetate 95:5 to50:50). Data for (2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol: ¹H NMR(500 MHz, CDCl₃) δ 7.98 (dd, J=8.8, 1.5, 1H), 7.89 (dd, J=11.7, 2.4,1H), 6.71 (dd, J=8.8, 8.8, 1H), 4.72 (bs, 1H), 3.81 (m, 1H), 3.73 (m,1H), 3.55 (m, 1H), 1.76 (m, 1H), 1.63 (m, 1H), 1.02 (t, J=7.8, 3H).

[0299](4R)-3-(2-Fluoro-4-nitrophenyl)-4-ethyl-2-(trifluoromethyl)-1.3-oxazolidine(Structure 37 of Scheme VIII, where R⁴=Et, R^(x)=CF₃). This compound wasprepared according to General Method 19 (EXAMPLE 45) from(2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol (1.6 g, 70 mmol),trifluoroacetaldehyde ethyl hemiacetal (4.9 g, 34 mmol) andp-toluenesulfonic acid (0.13 g, 0.68 mmol) in 70 mL anhydrous benzene toafford 1.8 g (85%) of(4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine,after flash chromatography (gradient elution, hexanes:ethyl acetate90:10 to 50:50). Data for(4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine: ¹HNMR (500 MHz, CDCl₃) δ 8.01 (m, 1H), 7.98 (m, 1H), 6.95 (dd, J=8.8, 8.8,1H), 5.68 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 3.92 (m, 1H), 2.00 (m,1H), 1.67 (m, 1H), 0.97 (t, J=7.8, 3H).

[0300] (2R)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol(Structure 38 of Scheme VIII, where R⁴=Et, R^(x)=CF₃). To a solution of(4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine(9.2 g, 29.8 mmol) and Et₃SiH (19.1 mL, 119 mmol) in 100 mL chloroformwas added BF₃OEt₂ (7.56 mL, 60 mmol). The reaction was heated to refluxfor 12 hrs, whereupon additional BF₃OEt₂ (7.56 mL, 60 mmol) was added,and the mixture heated at reflux for an additional 12 hrs. Aftercooling, MeOH (5 mL) was added and the reaction was allowed to stir atr.t. for an hour. The reaction was poured in water (250 mL) andextracted with ethyl acetate (3×250 mL). The organic layers werecombined, washed sequentially with water (250 mL) and brine (250 mL),dried (MgSO₄), filtered, and concentrated under reduced pressure to abrown oil. Flash chromatography (gradient elution, hexanes:ethyl acetate95:5 to 50:50) afforded 5.4 g (59%) of(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol. Datafor (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol: ¹HNMR (500 MHz, CDCl₃) δ 7.98 (dd, J=8.8, 2.4, 1H), 7.94 (dd, J=13.2, 2.9,1H), 7.37 (dd, J=8.8, 8.8, 1H), 4.12 (m, 1H), 3.87 (m, 1H), 3.77 (m,1H), 3.70 (m, 1H), 3.57 (m, 1H), 1.78 (dd, J=6.8, 4.4, 1H), 1.58 (dq,J=7.8, 2.9, 2H), 0.95 (t, J=7.3, 1H).

[0301](3R)-3-Ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 39 of Scheme VIII, where R⁴=Et, R^(x)=CF₃). This compound wasprepared according to General Method 20 from(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol (5.4 g,17.3 mmol) in 45 mL THF and NaH (1.4 g, 35 mmol) in 10 mL THF heated atreflux for 1 hr to afford 3.78 g (75%) of(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,after flash chromatography (gradient elution, hexanes:ethyl acetate 95:5to 50:50). Data for(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:¹H NMR (500 MHz, CDCl₃) δ 7.81 (dd, J=8.8, 2.4, 1H), 7.73 (d, J=2.9,1H), 6.72 (d, J=8.8, 1H), 4.34 (dd, J=11.2, 1.5, 1H), 4.13 (m, 1H), 4.03(dd, J=11.2, 2.4, 1H), 3.8 (m, 1H), 3.37 (m, 1H), 1.67 (m, 1H), 1.01 (t,J=7.3, 3H).

[0302](3R)-7-Amino-3-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 40 of Scheme VIII, where R⁴=Me, R^(x)=CF₃). This compound wasprepared according to General Method 4 (EXAMPLE 1) from(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(5.6 g, 19.3 mmol) and 10% Pd/C (cat.) in 60 mL ethyl acetate to afford4.8 g (95%) of(3R)-7-amino-3,4-dihydro-3-ethyl-4-trifluoroethyl-2H-1,4-benzoxazine asa tan solid, which was carried on directly to the next step.

[0303](2R)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 149, Structure 41 of Scheme VIII, where R¹=H,R²=trifluoromethyl, R⁴=Et, R^(x)=CF₃). This compound was prepared byGeneral Method 11 (EXAMPLE 22) from(3R)-7-amino-3-ethyl-3,4-dihydro-4-trifluoroethyl-2H-1,4-benzoxazine(4.8 g, 18.4 mmol) and ethyl-4,4,4-trifluoroacetoacetate (8.1 mL, 55.2mmol) in 58 mL toluene heated at reflux for 3 d, followed by workup andtreatment with 35 mL concentrated H₂SO₄ heated to 90° C. for 0.5 h toafford 1.5 g (21%) of Compound 149, a yellow solid, after flashchromatography (gradient elution, hexanes:ethyl acetate 95:5 to 50:50)followed by additional purification using reverse phase HPLC (KromasilC18, 50×250 mm; 65:35 MeOH:water; flow rate of 80 mL/min.). Data forCompound 149: ¹H NMR (500 MHz, CDCl₃) δ 11.75 (bs, 1H), 7.06 (s, 1H),6.91 (s, 1H), 6.89 (s, 1H), 6.89 (s, 1H), 4.34 (dd, J=10.7, 1.5, 1H),4.14 (dd, J=11.2, 2.4, 1H), 3.99 (m, 1H), 3.75 ( m, 1H), 3.28 (m, 1H),1.64 (dq, J=7.6, 7.3, 2H), 1.00 (t, J=7.3, 3H).

EXAMPLE 47(2R)-1,2,3,6-Tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 150, Structure 41 of Scheme VIII, where R¹=H,R²=Trifluoromethyl, R⁴=isobutyl, R^(x)=CF₃)

[0304] (2R)-2-(2-Fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol(Structure 36 of Scheme VIII, where R⁴=isobutyl). This compound wasprepared according to General Method 18 (EXAMPLE 45) from3,4-difluoronitrobenzene (8.73 g, 54.9 mmol),R-2-amino-4-methyl-1-pentanol (5.00 g, 42.7 mmol) in EtOH heated atreflux for 16 h to afford 6.0 g (55%) of(2R)-2-(2-fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol, a yellowsolid, after flash chromatography (gradient elution, hexanes:EtOAc 9:1to 1:1). Data for(2R)-2-(2-fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol: R_(f)0.3 (3:1hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.97 (m, 1 H), 7.90 (dd,1H, J=11.7, 2.7), 6.74 (dd, 1H, J=8.6, 8.6), 4.62-4.57 (m, 1H),3.82-3.74 (m, 1H), 3.75-3.62 (m, 2H), 1.77-1.65 (m, 1H), 1.61-1.45 (m,2H), 0.99 (d, 3H, J=6.6), 0.93 (d, 3H, J=6.6).

[0305](4R)-3-(2-Fluoro-4-nitrophenyl)-4-isobutyl-2-(trifluoromethyl)-1,3-oxazolidine(Structure 37 of Scheme VIII, where R⁴=isobutyl, R^(x)=CF₃. Thiscompound was prepared according to General Method 19 (EXAMPLE 45) from(2R)-2-(2-fluoro-4-nitrophenyl)amino-4-methyl-1-pentanol (6.0 g, 23mmol) trifluoroacetaldehyde ethyl hemiacetal (30.4 g, 211 mmol) andp-toluenesulfonic acid (0.020 g, 0.10 mmol) in 250 mL benzene to afford5.15 g (65%) of(4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidine.Data for(4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidineas a mixture of diastereomers: R_(f)0.8 (3:1 hexanes:EtOAc); ¹H NMR (400MHz, CDCl₃) δ 8.03-7.94 (m, 2H), 6.96-6.88 (m, 1H), 5.81 (q, 1H), minordiast., J=4.7), 5.69 (q, 1H, major diast., J=4.7), 4.45-4.40 (m, 1H,minor diast.), 4.36-4.28 (m, 1H, major diast.), 4.11-4.01 (m, 2H),1.82-1.74 (m, 1H), 1.66-1.52 (m, 2H), 1.02 (d, 3H, major diast., J=6.4),0.99-0.95 (m, 3H), 0.91 (d, 3H, minor diast., J=6.6).

[0306](2R)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol(Structure 38 of Scheme VIII, where R⁴=isobutyl, R^(x)=CF₃. To asolution of(4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidine(4.8 g, 14.3 mmol) and Et₃SiH (21.6 g, 186 mmol) in 60 mL chloroform wasadded BF₃OEt₂ (14.2, 60 mmol, added in portions) The reaction was heatedat reflux for 1 d After cooling, the reaction was poured in water (200mL) and extracted with chloroform (3×150 mL). The organic layers werecombined, washed sequentially with water (200 mL) and brine (200 mL),dried (MgSO₄), filtered, and concentrated under reduced pressure to abrown oil. Flash chromatography (gradient elution, hexanes:ethyl acetate95:5 to 3:1) afforded 2.1 g (44%) of(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol,an orange oil. Data for(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol:R_(f)0.8 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, 1H,J=9.3, 2.4), 7.94 (dd, 1H, J=12.9, 2.5), 7.40 (dd, 1H, J=8.7, 8.7),4.21-4.10 (m, 1H), 3.89-3.78 (m, 1H), 3.79-3.65 (m, 3H), 1.96-1.89 (m,1H), 1.67-1.54 (m, 1H), 1.55-1.44 (m, 1H), 1.32-1.22 (m, 1H), 0.91 (d,3H, J=6.6), 0.77 (d, 3H, J=6.6).

[0307](3R)-3,4-Dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 39 of Scheme VIII, where R⁴=isobutyl, R^(x)=CF₃. Thiscompound was prepared according to General Method 20 (EXAMPLE 45) from(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol(1.95 g, 5.76 mmol) in 30 mL THF and NaH (1.4 g, 35 mmol) in 25 mL THFheated at reflux for 1 hr to afford 0.87 g (50%) of(3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,a yellow oil. Data for(3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.6 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, 1H,J=9.1, 2.7), 7.71 (d, 1H, J=2.5), 6.72 (d, 1H, J=9.1), 4.30 (dd, 1H,ABx, J=11.0, 1.5), 4.19-4.06 (m, 1H), 4.06-4.01 (m, 1H), 3.82-3.73 (m,1H), 3.53-3.47 (m, 1H), 1.71-1.61 (m, 2H), 1.38-1.29 (m, 1H), 0.99 (d,3H, J=6.5), 0.96 (d, 3H, J=6.5).

[0308](3R)-7-Amino-3,4-dihydro-3-isobutyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 40 of Scheme VIII, where R⁴=isobutyl, R^(x)=CF₃). Thiscompound was prepared according to General Method 4 (EXAMPLE 1) from(3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(0.22 g, 0.69 mmol) and 10% Pd/C (0.075 g) in 5 mL ethyl acetate toafford 0.13 g (65%) of(3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine.Data for(3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine:R_(f)0.3 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 6.63 (d, 1H,J=8.5), 6.27 (dd, 1H, J=8.5, 2.6), 6.23 (d, 1H, J=2.5), 4.10 (dd, 1H,ABx, J=10.6, 1.8), 3.97 (dd, 1H, ABx, J=10.6, 2.3), 3.70-3.51 (m, 2H),3.38 (broad s, 2H), 3.19-3.13 (m, 1H), 1.75-1.63 (m, 1H), 1.47-1.25 (m,2H), 0.93 (d, 3H, J=6.6), 0.89 (d, 3H, J=6.6).

[0309](2R)-1,2,3,6-Tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 150, Structure 41 of Scheme VIII, where R¹=H,R²=trifluoromethyl, R⁴=isobutyl, R^(x)=CF₃). This compound was preparedby General Method 11 (EXAMPLE 22) from(3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine(0.13 g, 0.45 mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.25 g, 1.4mmol) in 6 mL toluene heated at reflux for 3 h, followed by workup andtreatment with 3 mL concentrated H₂SO₄ heated to 95° C. for 1 h toafford 17 mg (9%) of Compound 150, a yellow solid, after purification byflash chromatography (95:5 CH₂Cl₂:MeOH) and recrystallization fromEtOAc:hexanes. Data for Compound 150: R_(f)0.2 (19:1 CH₂Cl₂;MeOH); ¹HNMR (400 MHz, CDCl₃) δ 12.58 (broad s, 1H), 7.05 (broad s, 1H), 6.97 (s,1H), 6.91 (s, 1H), 4.30 (dd, 1H, ABX, J=11.0, 1.1), 4.16 (dd, 1H, ABX,J=11.0, 1.3), 4.01-3.91 (m, 1H), 3.75-3.65 (m, 1H), 3.42-3.37 (m, 1H),1.71-1.62 (m, 1H), 1.62-1.54 (m, 1H), 1.35-1.27 (m, 1H), 0.96 (d, 3H,J=6.9), 0.93 (d, 3H, J=7.5).

EXAMPLE 48(2R)-1,2,3,6-Tetrahydro-2-isopropyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 151, Structure 41 of Scheme VIII where R¹=H,R²=Trifluoromethyl, R⁴=isopropyl, R^(x)=CF₃)

[0310] (2R)-2-(2-Fluoro-4-nitrophenyl)amino-3-methyl-1-butanol(Structure 36 of Scheme VIII, where R⁴=isopropyl). This compound wasprepared according to General Method 18 (EXAMPLE 45) from3,4-difluoronitrobenzene (9.9 g, 62 mmol), R-2-amino-3-methyl-1-butanol(5.00 g, 48.5 mmol) in 6 mL EtOH heated at reflux for 22 h to afford 8.3g (71%) of (2R)-2-(2-fluoro-4-nitrophenyl)amino-3-methyl-1-butanol, ayellow solid, after flash chromatography. Data for(2R)-2-(2-fluoro-4-nitrophenyl)amino-3-methyl-1-butanol: R_(f)0.8 (1:1hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.00-7.96 (m, 1H), 7.90 (dd,1H, J=11.6, 2.4), 6.73 (dd, 1H, J=8.5, 8.5), 4.75-4.69 (m, 1H),3.87-3.79 (m, 1H), 3.79-3.70 (m, 1H), 3.47-3.39 (m, 1H), 2.06-1.97 (m,1H), 1.03 (d, 3H, J=3.6), 1.01 (d, 3H, J=3.6).

[0311](4R)-3-(2-Fluoro-4-nitrophenyl)-4-isopropyl-2-(trifluoromethyl)-1,3-oxazolidine(Structure 37 of Scheme VIII, where R⁴=isopropyl, R^(x)=CF₃. Thiscompound was prepared according to General Method 19 (EXAMPLE 45) from(2R)-2-(2-fluoro-4-nitrophenyl)amino-3-methyl-1-butanol (8.3 g, 34 mmol)trifluoroacetaldehyde ethyl hemiacetal (86.4 g, 0.600 mol) andp-toluenesulfonic acid (20 mg, 0.10 mmol) in 220 mL benzene to afford5.2 g (47%) of(4R)-3-(2-fluoro-4-nitrophenyl)-4-isopropyl-2-trifluoromethyloxazolidine.Data for(4R)-3-(2-fluoro-4-nitrophenyl)-4-isopropyl-2-trifluoromethyloxazolidine:R_(f)0.7 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.04-7.97 (m,2H), 7.22 (dd, 1H, J=8.7, 8.7), 5.34 (quartet, 1H, J=4.6), 4.27 (dd, 1H,J=8.0, 8.0), 4.11 (dd, 1H, J=7.4, 7.4), 3.81 (quartet, 1H, J=7.1),2.02-1.93 (m, 1H), 0.96 (d, 6H, J=6.8).

[0312](2R)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol(Structure 38 of Scheme VIII, where R⁴=isopropyl, R^(x)=CF₃. To asolution of(4R)-3-(2-fluoro-4-nitrophenyl)-4-isopropyl-2-trifluoromethyloxazolidine(1.8 g, 5.6 mmol) and Et₃SiH (1.88 g, 16.1 mmol) in 15 mL CHCl₃ wasadded TiCl₄ (6 mL of a 1M solution in CH₂Cl₂, 6 mmol) at −78° C. Thesolution was stirred for 2 h, then allowed to warm to 0° C. and stirredfor 2 h. The mixture was poured into 150 mL water and neutralized with6N NaOH. The aqueous layer was extracted with CHCl₃ (3×100 mL), and thecombined organic layers washed with brine (150 mL), dried over MgSO₄,filtered and concentrated. Flash chromatography (gradient elution,hexanes:EtOAc 9:1 to 3:1) afforded 1.6 g (88%) of(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol,an orange oil. Data for(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol:R_(f)0.3 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, 1H,J=8.8, 2.3), 7.92 (dd, 1H, J=13.4, 2.5), 7.37 (dd, 1H, J=8.8, 8.8),4.33-4.23 (m, 1H), 4.03-3.86 (m, 2H), 3.81-3.74 (m, 1H), 3.36-3.27 (m,1H), 1.97-1.88 (m, 1H), 1.85 (broad s, 1H), 0.99 (d, 3H, J=6.6), 0.94(d, 3H, J=6.6).

[0313](3R)-3,4-Dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 39 of Scheme VIII, where R⁴=isopropyl, R^(x)=CF₃. Thiscompound was prepared according to General Method 20 (EXAMPLE 45) from(2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol(1.58 g, 4.87 mmol) in 30 mL THF and NaH (0.351 g, 14.6 mmol) in 10 mLTHF heated at reflux for 0.5 hr to afford 0.80 g (54%) of(3R)-3,4-dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine,a yellow oil, after purification by flash chromatography (gradientelution, hexanes:EtOAc 9:1 to 3:1). Data for(3R)-3,4-dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.5 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, 1H,J=9.1, 2.5), 7.72 (d, 1H, J=2.6), 6.79 (d, 1H, J=9.1), 4.49 (dd, 1H,ABX, J=11.1, 0.92), 4.37-4.26 (m, 1H), 3.95 (dd, 1H, J=11.1, 2.4),3.80-3.69 (m, 1H), 3.14 (d, 1H, J=8.5), 2.08-1.98 (m, 1H), 1.01 (d, 3H,J=6.9), 0.99 (d, 3H, J=6.9).

[0314](3R)-7-Amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(Structure 40 of Scheme VIII, where R⁴=isopropyl, R^(x)=CF₃). Thiscompound was prepared according to General Method 4 (EXAMPLE 1) from(3R)-3,4-dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(0.350 g, 1.15 mmol) and 10% Pd/C (0.14 g) in 7 mL EtOAc to afford 0.284g (90%) of(3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazineafter purification by flash chromatography (gradient elution,hexanes:EtOAc 9:1 to 3:1). Data for(3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine:R_(f)0.2 (3:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 6.71 (d, 1H,J=8.5), 6.27 (dd, 1H, J=8.5, 2.6), 6.20 (d, 1H, J=2.5), 4.34 (dd, 1H,ABX, J=11.0, 1.5), 3.84 (dd, 1H, ABX, J=11.3, 2.2), 3.71-3.47 (m, 2H),3.41 (broad s, 2H), 2.62 (d, 1H, J=9.8), 1.81-1.70 (m, 1H), 0.98 (d, 3H,J=6.7), 0.96 (d, 3H, J=6.7).

[0315](2R)-1,2,3,6-Tetrahydro-2-isopropyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one(Compound 151, Structure 41 of Scheme VIII, where R¹=H,R²=trifluoromethyl, R⁴=isopropyl, R^(x)=CF₃). This compound was preparedaccording to General Method 11 (EXAMPLE 22) from(3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine(0.284 g, 1.04 mmol) and ethyl 4,4,4-trifluoroacetoacetate (0.573 g,3.11 mmol) in 8 mL toluene followed by workup and treatment with 6 mLconc. sulfuric acid to afford 0.15 g (38%) of Compound 151, a yellowsolid, after flash chromatography (19:1 CH₂Cl₂:MeOH). Furtherpurification was performed by reverse phase HPLC (ODS, 5 microm, 10×250mm), 80% MeOH:water, 2.6 mL/min). Data for Compound 151: R_(f)0.2 (19:1CH₂Cl₂;MeOH); ¹H NMR (400 MHz, CDCl₃) δ 12.52 (broad s, 1H), 7.14 (broads, 1H), 6.95 (s, 1H), 6.92 (s, 1H), 4.50 (d, 1H, J=11.0), 4.18-4.06 (m,1H), 4.05 (dd, 1H, ABX, J=11.0, 2.5), 3.75-3.60 (m, 1H), 2.98 (d, 1H,J=8.7), 1.98-1.88 (m, 1H), 1.00 (d, 3H, J=7.3), 0.98 (d, 3H, J=7.3).

EXAMPLE 49(±)-1,2,3,4,4a,5-Hexahydro-11-(trifluoromethyl)-pyrido[1′2′:4,5][1,4]oxazino[3,2-g]quinolin-9(8H)-one(Compound 152, Structure 41 of Scheme VIII, where R¹=H,R²=Trifluoromethyl, R⁴, R^(x)=—(CH₂)₃—)

[0316](±)-[1-(2-Fluoro-4-nitrophenyl)-2-piperidinyl]-methanol](Structure 42 ofScheme IX, where R⁴R^(x)=—(CH₂)₄—). A solution of3,4-difluoronitrobenzene (1.00 g, 6.28 mmol) and(±)-2-piperidinemethanol (0.724 g, 6.28 mmol) in 1.5 mL EtOH was heatedat 50° C. for 18 h, then heated at reflux for 24 h. The solvent wasconcentrated and the crude reaction purified by flash chromatography(7:3 hexanes:EtOAc) to afford 0.85 g (53%) of(±)-[1-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol], an orange oil.Data for (±)-[1-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol]:R_(f)0.36 (3:7, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.95 (dd, 1H,J=8.8, 2.4), 7.88 (dd, 1H, J=13.2, 2.4), 7.01 (t, 1H, J=8.8), 4.04-3.97(m, 2H), 3.74-3.68 (m, 1H), 3.45-3.42 (m, 1H), 3.34-3.28 (m, 1H),1.89-1.82 (m, 1H), 1.77-1.61 (m, 6H).

[0317] (±)-3-Nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine(Structure 39 of Scheme IX, where R⁴, R^(x)=—(CH₂)₄—). A suspension of(±)-[1-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol (0.586 g, 2.30mmol) and sodium hydride (60% mineral oil suspension, 0.101 g, 2.54mmol) in 10 mL THF was heated at reflux for 16 h. The mixture wasneutralized with phosphate buffer (pH 7), and the resultant solution wasextracted twice with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated. Flashchromatography (7:3 hexanes:EtOAc) afforded 0.410 g (76%) of(±)-3-nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine, ayellow-orange solid. Data for (±)-3-nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine: R_(f)0.71 (2:3,EtOAc:hexanes) ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, 1H, J=9.3, 2.9), 7.64(d, 1H, J=2.9), 6.75 (d, 1H, J=9.3), 4.23 (dd, 1H, J=10.7, 2.9), 3.96(dd, 1H, J=10.7, 7.8), 3.93 (m, 1H), 3.22-3.17 (m, 1H), 2.78 (td, 1H,J=12.8, 3.0), 1.95-1.92 (m, 1H), 1.88-1.84 (m, 1H), 1.75-1.71 (m, 1H),1.66-1.60 (m, 1H), 1.58-1.48 (m, 1H), 1.35-1.27 (m, 1H).

[0318] (±)-3-Amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine(Structure 40 of Scheme VIII, where R⁴, R^(x)=—(CH)₃—). This compoundwas prepared according to General Method 4 (EXAMPLE 1) from(±)-3-nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine (0.300g, 1.30 mmol) to afford 0.232 g (88%) of(±)-3-amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine, acolorless oil, after flash chromatography (gradient elution 3:7EtOAc:hexanes, then 3:2 EtOAc:hexanes). Data for(±)-3-amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine:R_(f)0.5 (2:3, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.66 (d, 1H,J=8.3), 6.24 (dd, 1H, J=8.5, 2.7), 6.21 (d, 1H, J=2.4), 4.11 (dd, 1H,J=10.7, 2.4), 3.97 (dd, 1H, J=10.7, 9.0), 3.69 (dd, 1H, J=13.7, 11.2),3.33 (br s, 2H), 2.85-2.80 (m, 1H), 2.43 (td, 1H, J=11.7, 2.9),1.87-1.78 (m, 2H), 1.69-1.60 (m, 2H), 1.45-1.36 (m, 1H), 1.28-1.19 (m,1H).

[0319](±)-1,2,3,4,4a,5-Hexahydro-11-(trifluoromethyl)-pyrido[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-9(8H)-one(Compound 152, Structure 41 of Scheme VIII, where R¹=H,R²=trifluoromethyl, R⁴, R^(x)=—(CH₂)₃—). This compound was preparedaccording to General Method 11 (EXAMPLE 22) from(±)-3-amino-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine (0.232g, 1.13 mmol), ethyl 4,4,4-trifluoroacetoacetate (0.250 g, 1.36 mmol) in11 mL benzene followed by treatment with conc. H₂SO₄ to afford 0.110 g(30%) of Compound 152, a yellow fluffy solid. Data for Compound 152:R_(f)0.15 (2:3, EtOAc:hexanes); ¹H NMR (400 MHz, CDCl₃) δ 10.73 (br s,1H), 7.09 (s, 1H), 6.87 (s, 1H), 6.73 (s, 1H), 4.26 (dd, 1H, J=10.5,2.6), 4.06 (dd, 1H, J=10.5, 9.0), 3.80 (m, 1H), 3.02-2.97 (m, 1H), 2.60(td, 1H, J=12.2, 2.9), 1.92 (m, 2H), 1.74-1.65 (m, 2H), 1.50-1.42 (m,1H), 1.29-1.21 (m, 1H).

EXAMPLE 50(R)-2,3,3a,4-Tetrahydro-10-(trifluoromethyl)-1H-pyrrolo[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one(Compound 153, Structure 41 of Scheme VIII, where R¹=H,R²=Trifluoromethyl, R⁴, R^(x)=—(CH₂)₂—)

[0320] (R)-[1-(2-Fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol(Structure 42 of Scheme IX, where R⁴, R^(x)=—(CH₂)₂—). A suspension of3,4-difluoronitrobenzene (1.57 g, 9.8 mmol), (R)-2-pyrrolidinemethanol(1.0 g, 9.8 mmol) and K₂CO₃ (1.36 g, 9.8 mmol) in 30 mL DMF was heatedat 75° C. for 20 h, whereupon the mixture was partitioned between water(100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc(100 mL), and the combined organic layers washed with brine, dried overNa₂SO₄, filtered, and concentrated. Flash chromatography (19:1CH₂Cl₂:MeOH) afforded 2.27 g (96%) of(R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol, an orangesolid. Data for(R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol: R_(f)0.17 (7:3hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) 7.94 (dd, 1H, J=9.1, 2.6), 7.89(dd, 1H, J=14.4, 2.6), 6.68 (t, 1H, J=9.0), 4.25-4.32 (m, 1H), 3.60-3.75(m, 3H), 3.40-3.50 (m, 1H), 1.95-2.15 (m, 4H), 1.43 (t, 1H, J=5.8).

[0321] (R)-2,3,3a,4-Tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine(Structure 42 of Scheme IX, where R⁴, R^(x)=—(CH₂)₂—). A suspension of(R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol (2.27 g, 9.4mmol) and NaH (60% mineral oil suspension, 0.737 g, 18.9 mmol) in 35 mLTHF was heated at reflux for 1 h. The reaction was quenched withphosphate buffer, and the aqueous layer was extracted with EtOAc. Thesolution was filtered through Celite, and the organic layer was washedwith brine, dried over MgSO₄, filtered, and concentrated. Flashchromatography (3:2 EtOAc:hexanes) afforded 476 mg (22%) of(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine, anorange solid. Data for(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine:R_(f)0.55 (3:2 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.87 (dd, 1H,J=9.2, 2.4), 7.74 (d, 1H, J=2.4), 6.44 (d, 1H, J=8.8), 4.56 (dd, 1H,J=10.3, 3.4), 3.65-3.72 (m, 1H), 3.60 (broad t, 1H, J=8.6), 3.44 (t, 1H,J=10.0), 3.36 (td, 1H, J=9.8, 7.3), 2.15-2.25 (m, 2H), 2.05-2.15 (m,1H), 1.45-1.55 (m, 1H).

[0322] (R)-7-Amino-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine(Structure 40 of Scheme VIII, where R⁴, R^(x)=—(CH₂)₂—). This compoundwas prepared according to General Method 4 (EXAMPLE 1) from(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine (0.470g, 2.10 mmol) to afford 0.39 g (98%) of(R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine. Datafor (R)-7-amino-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine:R_(f)0.55 (3:2 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 6.50 (d, 1H,J=8.3), 6.32 (d, 1H, J=2.4), 6.29 (dd, 1H, J=8.3, 2.4), 4.31 (dd, 1H,J=8.3, 1.5), 3.37-3.50 (m, 3H), 3.31 (broad s, 2H), 3.13 (broad q, 1H,J=8.3), 2.07-2.15 (m, 1H), 1.90-2.05 (m, 2H), 1.40-1.50 (m, 1H).

[0323](R)-2,3,3a,4-Tetrahydro-10-(trifluoromethyl)-1H-pyrrolo[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one(Compound 153, Structure 41 of Scheme VIII, where R¹=H,R²=trifluoromethyl, R⁴, R^(x)=—(CH₂)₂—). This compound was preparedaccording to General Method 11 (EXAMPLE 22) from(R)-7-amino-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine (0.390g, 2.05 mmol) and ethyl 4,4,4-trifluoroacetoacetate (0.378 g, 2.05 mmol)in 14 mL benzene, followed by workup and treatment with 7 mLconcentrated sulfuric acid to afford 120 mg (20%) of Compound 153, ayellow solid after flash chromatography (92:8 CH₂Cl₂:MeOH). Furtherpurification was performed by reverse phase HPLC (ODS, 5 micron, 10×250mm, 3 mL/min). Data for Compound 153: ¹H NMR (400 MHz, CDCl₃) δ 11.42(broad s, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.76 (broad s, 1H), 4.54 (dd,1H, J=9.6, 2.7), 3.61 (t, 1H, J=9.6), 3.50-3.60 (m, 1H), 3.40-3.50 (m,1H), 3.30-3.40 (m, 1H), 2.12-2.22 (m, 2H), 2.00-2.10 (m, 1H), 1.40-1.50(m, 1H).

EXAMPLE 511,3,4,6-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-2,7-dione(Compound 154, Structure 47 of Scheme X, where R¹=H, R²=Trifluoromethyl,R⁶=R⁷=R¹³=Me)

[0324] 3,4-Dihydro-3,3-dimethylquinoxalin-2(1H)-one (Structure 44 ofScheme X, where R⁶=R⁷=Me). In a 200-mL r.b. flask, a solution of1,2-phenylenediamine (2.12 g, 19.6 mmol), diisopropylethylamine (4.55ml, 25.5 mmol, 1.3 equiv), ethyl-2-bromoisobutyrate (4.97 mL, 25.5 mmol,1.3 equiv) in DMF (20 mL) was heated to 110° C. overnight, cooled,partitioned between EtOAc (100 mL) and H₂O (30 mL). The aqueous layerwas extracted with EtOAc (2×50 mL). The combined organic layers werewashed sequentially with 1 M HCl (40 mL), H₂O (40 mL), saturated NaHCO₃(40 ml), H₂O (40 mL) and brine (30 mL), dried (MgSO₄), filtered, andconcentrated. The crude product was purified by recrystallization(CH₂Cl₂/hexane) to give 2.09 g (60%) of3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one as white crystals. Data for3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one: ¹H NMR (400 MHz, CDCl₃) δ7.84 (bs, 1H), 6.89 (dd, J=7.3, 7.3, 1H), 6.76 (dd, J=7.2, 7.3, 1H),6.70 (d, J=7.6, 1H), 6.67 (d, J=6.9, 1H), 3.69 (bs, 1H), 1.41 (s, 6H).

[0325] 3,4-Dihydro-1,3,3-trimethylquinoxalin-2(1H)-one. In a 200-mL r.b.flask, a solution of 3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one (1.00g, 5.66 mmol) in dry THF was treated with NaH (0.28 g, 7.09 mmol, 1.25equiv). The reaction mixture was stirred at room temperature for 30minutes before iodomethane (0.39 mL, 6.24 mmol, 1.1 equiv) was added tothe reaction flask. The reaction was then stirred at room temperatureovernight then partitioned between EtOAc (100 mL) and H₂O (20 mL). Theaqueous layer was extracted with EtOAc (2×30 mL). The combined organiclayers were then washed with brine (20 mL), dried (MgSO₄), filtered, andconcentrated to a thick oil. Purification by flash chromatography (25%EtOAc/hexane) afforded 830 mg (78%) of3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one as a white solid. Datafor 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one: ¹H NMR (400 MHz,CDCl₃) δ 6.90 (m, 3H), 6.67 (d, J=7.7, 1H), 3.69 (bs, 1H), 3.36 (s, 3H),1.37 (s, 6H).

[0326] 3,4-Dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one(Structure 45 of Scheme X, where R⁶=R⁷=R¹³=Me). In a 50-mL r.b. flask, asolution of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one (830 mg,4.36 mmol) in 20 mL of conc. H₂SO₄ was cooled to −15° C. A solution ofHNO₃ (336 mg, 4.80 mmol, 1.1 equiv) dissolved in conc. H₂SO₄ (1 mL) wasthen added dropwise via syringe in order to maintain a temperature below−5° C. After complete addition the reaction was allowed to stir at −15°C. for 15 min, warmed to rt, poured over NaOH (15 g) pellets and ice.After complete solution of the NaOH pellets, the red precipitate wasfiltered, redissolved in EtOAc (150 mL), washed with H₂O (20 mL), brine(20 mL), dried (MgSO₄), filtered, and concentrated to give a orangesolid. No further purification is required to obtain 960 mg (94%) of3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one as an orangesolid. Data for 3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one:¹H NMR (400 MHz, CDCl₃) δ 7.76 (dd, J=8.8, 2.5, 1H), 7.55 (d, J=2.4,1H), 6.96 (d, J=8.9, 1H), 4.04 (bs, 1H), 3.42 (s, 3H), 1.41 (s, 6H).

[0327] 6-Amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one(Structure 46 of Scheme X, where R⁶=R⁷=R¹³=Me). In a Parr shakerapparatus, a solution3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one (960 mg, 4.08mmol) in 50 mL of EtOAc:EtOH (1:1) and a catalytic amount of 10% Pd onactivated carbon (96 mg, 10 wt-%) were shaken under an atmosphere ofhydrogen gas at 45 psi overnight. The reaction mixture was filteredthrough a pad of celite. The filtrate and EtOH washings were combinedand concentrated to give 838 mg (100%) of6-amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one, purple brownsolid. Data for 6-amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one:¹H NMR (400 MHz, CDCl₃) δ 6.69 (d, J=8.42, 1H), 6.19 (dd, J=8.5, 2.4,1H), 6.05 (d, J=2.4, 1H), 3.55 (bs, 1H), 3.31 (s, 3H), 1.35 (s, 6H).

[0328]1,3,4,6-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-2.7-dione(Compound 154, Structure 47 of Scheme X, where R¹=H, R²=trifluoromethyl,R⁶=R⁷R¹³=Me). In a 100-mL r.b. flask, a solution of6-amino-3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one (500 mg, 2.44mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.46 mL, 3.16 mmol, 1.3equiv) in toluene (40 mL) was heated to reflux with stirring overnight.Removal of solvent followed be treatment of the crude product with concH₂SO₄ (10 mL) at 100° C. for 10 h, cooled to rt, poured onto ice and thepH adjusted to 7 with NaOH pellets. The aqueous phase was extracted withEtOAc (4×50 mL), combined, washed with brine, dried (MgSO₄), filtered,and concentrated to a brown oil. Purification by flash chromatography(EtOAc/hexane, 25% to 50%, gradient elution) afforded 80 mg (10%) ofCompound 154 as a yellow solid. Data for Compound 154: ¹H NMR (400 MHz,DMSO-d₆) δ 12.07 (s, 1H), 7.22 (s, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 6.61(s, 1H), 3.30 (s, 3H), 1.29 (s, 6H).

EXAMPLE 521,2,3,4-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-7(6H)-one(Compound 155, Structure 49 of Scheme X, where R¹=H, R²=Trifluoromethyl,R⁶=R⁷=R¹³=Me)

[0329]1,2,3,4-Tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-2-one(Structure 48 of Scheme X, where R¹=H, R²=trifluoromethyl,R⁶=R⁷=R¹³=Me). This compound was made according to General Method 12(EXAMPLE 22) from Compound 154 (EXAMPLE 51) (40 mg, 0.12 mmol), cesiumfluoride (28 mg, 0.18 mmol, 1.5 equiv), and 2-iodopropane (0.02 mL, 0.18mmol, 1.5 equiv). The crude reaction mixture was purified by silica gelchromatography (EtOAc/hexane, 25% to 50% gradient elution) to afford 26mg (56%) of1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-2-oneas an off-white solid. Data for1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-2-one:¹H NMR (400 MHz, CDCl₃) δ 7.34 (s, 1H), 7.06 (s, 1H), 6.96 (s, 1H), 5.49(sep, J=6.3, 1H), 4.17 (s, 1H), 3.47 (s, 3H), 1.45 (s, 6H), 1.39 (d,J=6.3, 6H).

[0330]1,2,3,4-Tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinoline.This compound was made according to General Method 2 (EXAMPLE 1) from1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-2-one(25 mg, 0.07 mmol) and BH₃-DMS (0.14 mL, 0.27 mmol, 4.0 equiv).Purification by silica gel chromatography (EtOAc/hexane, 10% to 25%gradient) afforded 5 mg (25%) of1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolineas a pale yellow solid. Data for1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinoline:¹H NMR (400 MHz, CDCl₃) δ 6.84 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 5.43(sept, J=6.1, 1H), 3.04 (s, 2H), 3.02 (s, 3H), 1.39 (d, J=6.0, 6H), 1.29(s, 6H).

[0331]1,2,3,4-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinolin-7(6H)-one(Compound 155, Structure 49 of Scheme X, where R¹=H, R²=trifluoromethyl,R⁶=R⁷=R¹³=Me). This compound was made according to General Method 15(EXAMPLE 22) from1,2,3,4-tetrahydro-7-isopropoxy-1,3,3-trimethyl-9-(trifluoromethyl)pyrazino[3,2-g]quinoline(5 mg, 0.02 mmol) to yield 2 mg (45%) of Compound 155, a yellow solid.Data for Compound 155: ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (broad s, I1H),6.97 (s, 1H), 6.39 (s, 1H), 6.37 (s, 1H), 5.23 (bs, 1H), 2.86 (s, 2H),2.82 (s, 3H), 1.17 (s, 6H).

EXAMPLE 539-(Trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one(Compound 156, Structure 54 of Scheme XI, where R⁴=H)

[0332] 6-Bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline(Structure 51 of Scheme XI). This compound was prepared according toGeneral Method 11 (EXAMPLE 22) from 4-bromo-3-chloroaniline (2.06 g,10.0 mmol), ethyl 4,4,4-trifluoroacetoacetate (2.30 g, 12.5 mmol) in 50mL toluene followed by heating in 33 mL conc. H₂SO₄ to afford 2.08 g(64%) of 6-bromo-7-chloro-4-(trifluoromethyl)-quinolin-2(1H)-one, anoff-white solid. This material was converted to the corresponding iminoether according to General Method 12 (EXAMPLE 22) with isopropyl iodide(4.32 g, 25.4 mmol) and CsF (3.85 g, 25.4 mmol) in 32 mL DMF to afford1.34 g (57%) of6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline, a whitesolid, after flash chromatography (hexanes). Data for6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline: ¹H NMR (400MHz, CDCl₃) δ 8.22 (broad s, 1H), 8.00 (s, 1H), 7.17 (s, 1H), 5.51(hept, 1H, J=6.2), 1.40 (d, 6H, J=6.2).

[0333]2-{[6-Bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine(Structure 52 of XI, where R⁴=H). A solution of6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline (0.500 g,1.36 mmol), 2-aminoethanethiol hydrochloride (0.185 g, 1.63 mmol), NaH(60% in mineral oil, 0.136 g, 3.40 mmol) in 6.8 mL DMF was stirred at 0°C., then allowed to warm to rt. After 4 h, the mixture was poured into acold saturated NH₄Cl:water (60 mL, 1:1). The solution was extracted withEtOAc (2×60 mL), and the combined organic layers washed sequentiallywith water (30 mL), brine (30 mL), dried over MgSO₄, filtered, andconcentrated. Flash chromatography (9:1 CH₂Cl₂:MeOH) afforded 0.404 g(73%) of2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine,a yellow-brown solid. Data for2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine:¹H NMR (400 MHz, CDCl₃) δ 8.13 (broad s, 1H), 7.63 (s, 1H), 7.10 (s,1H), 5.54 (hept, 1H, J=6.2), 3.17-3.25 (m, 2H), 3.08-3.15 (m, 2H), 1.41(d, 6H, J=6.2).

[0334]2,3-Dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(Structure 53 of Scheme XI, where R⁴=H). A 10 mL Schlenk flask wascharged with palladium acetate (10.7 mg, 0.0476 mmol), R-BINAP (32.6 mg,0.0524 mmol) and sodium t-butoxide (0.137 g, 1.43 mmol). The flask wasplaced under vacuum, then bled with nitrogen. This process was repeatedtwice. The solids were dissolved in 3 mL toluene, and a solution of2-{[6-bromo-2-isopropoxy-4-(trifluoromethyl)-7-quinolinyl]sulfanyl}-1-ethanamine(0.390 g, 0.953 mmol) in 3.3 mL toluene was added. The flask was heatedto 100° C. for 4 h, whereupon the reaction was quenched with sat'd NH₄Cl(30 mL) and water (30 mL). The mixture was extracted with EtOAc (2×60mL), and the combined organic layers washed with brine (30 mL), driedover MgSO₄, filtered, and concentrated. Flash chromatography (4:1hexanes:EtOAc) afforded 0.242 g (77%) of2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline,a yellow solid. Data for2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline:¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 6.99 (s, 1H), 6.90 (broad s,1H), 5.44 (hept, 1H, J=6.2), 4.35 (broad s, 1H), 3.64-3.70 (m, 2H),3.11-3.16 (m, 2H), 1.37 (d, 6H, J=6.2).

[0335]9-(Trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one(Compound 156, Structure 54 of Scheme XI, where R⁴=H). This compound wasprepared according to General Method 15 (EXAMPLE 22) from2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(15 mg, 0.046 mmol) and 0.15 mL conc. HCl and 0.5 mL HOAc to afford 12mg (91%) of Compound 156, a yellow solid. Data for Compound 156: ¹H NMR(400 MHz, ace-d₆) δ 10.8 (v broad s, 1H), 7.12 (s, 1H), 6.92 (broad s,1H), 6.75 (s, 1H), 5.74 (broad s, 1H), 3.58-3.64 (m, 2H), 3.12-3.20 (m,2H).

EXAMPLE 541-Methyl-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one(Compound 157, Structure 56 of Scheme XI, where R⁴=H, R^(x)=Me)

[0336]2,3-Dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(Structure 55 of Scheme XI, where R⁴=H, R^(x)=Me). To a solution of2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(11 mg, 0.033 mmol) and paraformaldehyde (9.9 mg, 0.33 mmol) in 0.5 mLacetic acid was added NaBH₃CN (12 mg, 0.19 mmol). After 16 h, thesolution was quenched with sat'd NaHCO₃ (20 mL), and was extracted withEtOAc (20 mL). The organic layer was washed sequentially with sat'dNaHCO₃ (10 mL) and brine (10 mL), dried over MgSO₄, filtered andconcentrated to afford 11 mg (97%) of2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline,a yellow solid. Data for2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline:¹H NMR (400 MHz, CDCl₃) δ 7.60 (s, 1H), 7.01 (s, 1H), 6.98 (broad s,1H), 5.45 (hept, 1H, J=6.2), 3.58-3.64 (m, 2H), 3.14-3.20 (m, 2H), 3.05(s, 3H), 1.37 (d, 6H, J=6.2).

[0337]1-Methyl-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one(Compound 157, Structure 56 of Scheme XI, where R⁴=H, R^(x)=H). Thiscompound was prepared according to General Method 15 (EXAMPLE 22) from2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(11 mg, 0.032 mmol) and 0.2 mL HCl and 0.6 mL HOAc heated at 80° C. for3 h to afford 7 mg (73%) of Compound 157, a yellow solid, after flashchromatography (23:2 CH₂Cl₂:MeOH). Data for Compound 157: ¹H NMR (400MHz, CDCl₃) δ 11.5 (broad s, 1H), 7.11 (s, 1H), 6.95 (s, 1H), 6.90(broad s, 1H), 3.52-3.60 (m, 2H), 3.15-3.20 (m, 2H), 3.01 (s, 3H).

EXAMPLE 551-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one(Compound 158, Structure 56 of Scheme XI, where R⁴=H, R^(x)=CF₃)

[0338]2,3-Dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(Structure 55 of Scheme XI, where R⁴=H, R^(x)=CF₃).

[0339] This compound was prepared according to General Method 7 (EXAMPLE5) from2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(11 mg, 0.034 mmol), trifluoroacetaldehyde ethyl hemiacetal (49 mg, 0.34mmol) and NaBH₃CN (14 mg, 0.22 mmol) in 0.7 mL TFA to afford 7.8 mg(56%) of2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline,a yellow oil, after flash chromatography (9:1 hexanes:EtOAc). Data for2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline:¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.21 (broad s, 1H), 7.03 (s,1H), 5.46 (hept, 1H, J=6.1), 3.97 (q, 2H, J=8.8), 3.77-3.83 (m, 2H),3.08-3.14 (m, 2H), 1.38 (d, 6H, j=6.1).

[0340]1-(2,2,2-Trifluoroethyl)-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one(Compound 158, Structure 56 of Scheme XI, where R⁴=H, R^(x)=CF₃). Thiscompound was prepared according to General Method 15 (EXAMPLE 22) from2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline(7.8 mg, 0.019 mmol) in 0.2 mL HCl and 0.6 mL HOAc to afford 3.6 mg(51%) of Compound 158, a yellow solid, after flash chromatography (23:2CH₂Cl₂:MeOH). Data for Compound 158: ¹H NMR (400 MHz, ace-d₆) δ10.8(broad s, 1H), 7.21 (s, 1H), 7.15 (broad s, 1H), 6.80 (s, 1H), 4.18 (q,2H, J=9.3), 3.77-3.83 (m, 2H), 3.18-3.24 (m, 2H).

EXAMPLE 56 Steroid Receptor Activity

[0341] Utilizing the “cis-trans” or “co-transfection” assay described byEvans et al., Science, 240:889-95 (May 13, 1988), the disclosure ofwhich is herein incorporated by reference, the compounds of the presentinvention were tested and found to have strong, specific activity asboth agonists, partial agonists and antagonists of AR. This assay isdescribed in further detail in U.S. Pat. Nos. 4,981,784 and 5,071,773,the disclosures of which are incorporated herein by reference.

[0342] The co-transfection assay provides a method for identifyingfunctional agonists and partial agonists that mimic, or antagonists thatinhibit, the effect of native hormones, and quantifying their activityfor responsive IR proteins. In this regard, the co-transfection assaymimics an in vivo system in the laboratory. Importantly, activity in theco-transfection assay correlates very well with known in vivo activity,such that the co-transfection assay functions as a qualitative andquantitative predictor of a tested compounds in vivo pharmacology. See,e.g., T. Berger et al. 41 J. Steroid Biochem. Molec. Biol. 773 (1992),the disclosure of which is herein incorporated by reference.

[0343] In the co-transfection assay, a cloned cDNA for an IR (e.g.,human PR, AR or GR) under the control of a constitutive promoter (e.g.,the SV 40 promoter) is introduced by transfection (a procedure to inducecells to take up foreign genes) into a background cell substantiallydevoid of endogenous IRs. This introduced gene directs the recipientcells to make the IR protein of interest. A second gene is alsointroduced (co-transfected) into the same cells in conjunction with theIR gene. This second gene, comprising the cDNA for a reporter protein,such as firefly luciferase (LUC), controlled by an appropriate hormoneresponsive promoter containing a hormone response element (HRE). Thisreporter plasmid functions as a reporter for thetranscription-modulating activity of the target IR. Thus, the reporteracts as a surrogate for the products (mRNA then protein) normallyexpressed by a gene under control of the target receptor and its nativehormone.

[0344] The co-transfection assay can detect small molecule agonists orantagonists of target IRs. Exposing the transfected cells to an agonistligand compound increases reporter activity in the transfected cells.This activity can be conveniently measured, e.g., by increasingluciferase production, which reflects compound-dependent, IR-mediatedincreases in reporter transcription. To detect antagonists, theco-transfection assay is carried out in the presence of a constantconcentration of an agonist to the target IR (e.g., progesterone for PR)known to induce a defined reporter signal. Increasing concentrations ofa suspected antagonist will decrease the reporter signal (e.g.,luciferase production). The co-transfection assay is therefore useful todetect both agonists and antagonists of specific IRs. Furthermore, itdetermines not only whether a compound interacts with a particular IR,but whether this interaction mimics (agonizes) or blocks (antagonizes)the effects of the native regulatory molecules on target geneexpression, as well as the specificity and strength of this interaction.

[0345] The activity of selected steroid receptor modulator compounds ofthe present invention were evaluated utilizing the co-transfectionassay; and in standard IR binding assays, according to the followingillustrative Examples.

[0346] Co-Transfection Assay

[0347] CV-1 cells (African green monkey kidney fibroblasts) werecultured in the presence of Dulbecco's Modified Eagle Medium (DMEM)supplemented with 10% charcoal resin-stripped fetal bovine serum(CH-FBS) then transferred to 96-well microtiter plates one day prior totransfection.

[0348] To determine AR agonist and antagonist activity of the compoundsof the present invention, the CV-1 cells were transiently transfected bycalcium phosphate coprecipitation according to the procedure of Bergeret al., 41 J. Steroid Biochem. Mol. Biol., 733 (1992) with the followingplasmids: pRShAR (5 ng/well), MTV-LUC reporter (100 ng/well), pRS-β-Gal(50 ng/well) and filler DNA (pGEM; 45 ng/well). The receptor plasmid,pRShAR, contains the human AR under constitutive control of the SV-40promoter, as more fully described in J. A. Simental et al.,“Transcriptional activation and nuclear targeting signals of the humanandrogen receptor”, 266 J. Biol. Chem., 510 (1991).

[0349] The reporter plasmid, MTV-LUC, contains the cDNA for fireflyluciferase (LUC) under control of the mouse mammary tumor virus (MTV)long terminal repeat, a conditional promoter containing an androgenresponse element. See e.g., Berger et al. supra. In addition, pRS-β-Gal,coding for constitutive expression of E. coli β-galactosidase (β-Gal),was included as an internal control for evaluation of transfectionefficiency and compound toxicity.

[0350] Six hours after transfection, media was removed and the cellswere washed with phosphate-buffered saline (PBS). Media containingreference compounds (i.e. progesterone as a PR agonist, mifepristone((11beta,17beta)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one:RU486; Roussel Uclaf) as a PR antagonist; dihydrotestosterone (DHT;Sigma Chemical) as an AR agonist and 2-OH-flutamide (the activemetabolite of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]pronanamide;Schering-Plough) as an AR antagonist; estradiol (Sigma) as an ER agonistand ICI 164,384 (N-butyl-3,17-dihydroxy-N-methyl-(7-alpha,17-beta)-estra-1,3,5(10)-triene-7-undecanamide; ICI Americas) as an ERantagonist; dexamethasone (Sigma) as a GR agonist and RU486 as a GRantagonist; and aldosterone (Sigma) as a MR agonist and spironolactone((7-alpha-[acetylthio]-17-alpha-hydroxy-3-oxopregn-4-ene-21-carboxylicacid gamma-lactone; Sigma) as an MR antagonist) and/or the modulatorcompounds of the present invention in concentrations ranging from 10⁻¹²to 10⁻⁵ M were added to the cells. Three to four replicates were usedfor each sample. Transfections and subsequent procedures were performedon a Biomek 1000 automated laboratory work station.

[0351] After 40 hours, the cells were washed with PBS, lysed with aTriton X-100-based buffer and assayed for LUC and β-Gal activities usinga luminometer or spectrophotometer, respectively. For each replicate,the normalized response (NR) was calculated as:

LUC response/β-Gal rate

[0352] where β-Gal rate=β-Gal/β-Gal incubation time.

[0353] The mean and standard error of the mean (SEM) of the NR werecalculated. Data was plotted as the response of the compound compared tothe reference compounds over the range of the dose-response curve. Foragonist experiments, the effective concentration that produced 50% ofthe maximum response (EC₅₀) was quantified. Agonist efficacy was afunction (%) of LUC expression relative to the maximum LUC production bythe reference agonist for PR, AR, ER, GR or MR. Antagonist activity wasdetermined by testing the amount of LUC expression in the presence of afixed amount of DHT as an AR agonist and progesterone as a PR agonist atthe EC₅₀ concentration. The concentration of test compound thatinhibited 50% of LUC expression induced by the reference agonist wasquantified (IC₅₀). In addition, the efficacy of antagonists wasdetermined as a function (%) of maximal inhibition. TABLE 1 Agonist,partial agonist, antagonist and binding activity of androgen receptormodulator compounds of present invention and the reference agonistcompound, dihydrotestosterone (DHT), and reference antagonists compound,2-hydroxyflutamide (Flut) and Casodex (Cas), on hAR in CV-1 cells. ARAgonist AR Antagonist CV-1 Cells CV-1 Cells Cmpd Efficacy PotencyEfficacy Potency No. (%) (nM) (%) (nM) 101 56 18 na na 102 na¹ na 58 22103 92 6.4 24 8000 104 na na 68 26 105 88 3.5 na na 106 80 4 na na 10792 26 na na 108 80 14 na na 109 na na 57 24 110 90 44 na na 111 88 2.4na na 112 80 2.6 na na 113 na na 78 61 114 94 6.2 na na 115 82 7.8 na na116 24 39 35 14 117 36 40 na na 118 76 11 na na 119 20 39 na na 120 nana 69 112 121 69 1.4 na na 122 na na 75 632 123 91 3.4 na na 124 54 3.6na na 125 74 0.70 na na 128 na na 42 1345 129 42 1340 76 13 130 48 8.9na na 131 46 31 na na 132 72 1.7 na na 137 na na 84 18 145 69 6 30 5024DHT 100 6 na na Fluox 120 2.8 na na Flut na na 83 25 Cas na na 81 201

[0354] TABLE 2 Overall agonist and antagonist potency of selectedandrogen receptor modulator compounds of present invention and thereference agonist and antagonist compounds shown in Table 1 on PR, AR,ER, GR and MR. GR MR PR Potency AR Potency ER Potency Potency PotencyCmpd Agon Antag Agon Antag Agon Antag Antag Antag No. (nM) (nM) (nM)(nM) (nM) (nM) (nM) (nM) 101 na na 18 na na na 6500 na 102 na 4100 na 22na 5900 3200 na 103 na 4500 6.4 8000 na na na na 104 na 2000 na 26 na na830 1800 105 na 3000 3.5 na na na 6700 na 114 na na 6.2 na na na na na121 na 415 1.4 na na na 1050 2570 123 na 2470 3.4 na na na 3160 na 137na na na 18 na na na na Fluox 1210 224 2.8 na na na 263 193 Prog 4 na1300 na na na na nt RU486 na 0.1 na 12 na 1500 0.7 1100 DHT na 1800 6 na1700 na na nt Flut na 1900 na 26 na na na na Estr nt nt na na 7 na na ntICI 164 na na na na na 160 na na Spir nt 268 nt nt na na 2000 25

EXAMPLE 57

[0355] The activity of selected compounds of the present invention as ARagonists was investigated in an immature castrated male rat model, arecognized test of the androgen activity of a given compound, asdescribed in L. G. Hershberger et al., “Myotrophic Activity of19-Nortestosterone and Other Steroids Determined by Modified Levator AniMuscle Method” 83 Proc. Soc. Exptl. Biol. Med., 175 (1953), and P. C.Walsh and R. F. Gittes, “Inhibition of extratesticular stimuli toprostatic growth in the castrated rat by antiandrogens”, 86Endocrinology, 624 (1970); the disclosures of which are hereinincorporated by reference.

[0356] The basis of this assay is the fact that the male sexualaccessory organs, such as the prostate and seminal vesicles, play animportant role in reproductive function. These glands are stimulated togrow and are maintained in size and secretory function by the continuedpresence of serum testosterone (T), which is the major serum androgen(>95%) produced by the Leydig cells in the testis under the control ofthe pituitary luteinizing hormone (LH) and follicle stimulating hormone(FSH). Testosterone is converted to the more active form,dihydrotestosterone (DHT), within the prostate by 5-alpha-reductase.Adrenal androgens also contribute about 20% of total DHT in the ratprostate, and about 40% of that in 65-year-old men. F. Labrie et al. 16Clin. Invest. Med., 475-492 (1993). However, this is not a majorpathway, since in both animals and humans, castration leads to almostcomplete involution of the prostate and seminal vesicles withoutconcomitant adrenalectomy. Therefore, under normal conditions, theadrenals do not support significant growth of prostatic tissue. M. C.Luke and D. S. Coffey, “The Physiology of Reproduction” ed. by E. Knobiland J. D. Neill, 1, 1435-1487 (1994). Since the male sex organs are thetissues most responsive to modulation of androgen activity, this modelis used to determine the androgen-dependent growth of the sex accessoryorgans in immature castrated rats. In addition to the prostate andseminal vesicles, the levator ani demonstrates androgen dependent growth(Herschberger, supra). Androgens which show the greatest levator anigrowth also show the greatest anabolic activity by nitrogen retentionmethods. Hence, the levator ani is a useful endpoint to measuremyotrophic effects on muscle. Compounds which show anabolic activitiescould be useful in the treatment of muscle-wasting disorders. Further,compounds which possess such anabolic activity without concomitantandrogenic activity (tissue selectivity) would be of practicaltherapeutic value. Male immature rats (50-60 g, 21-day-old,Sprague-Dawley, Harlan) were castrated under metofane anesthesia.Immediately after surgery, animals groups were dosed for 3 days asfollows:

[0357] (1) control vehicle;

[0358] (2) Fluoxymesterone (Fluox) (1.0, 3.0, and 100 mg/kg, oraladministration daily); and

[0359] (3) a compound of the present invention (different doses, oraladministration daily) to demonstrate agonist activity

[0360] At the end of the 3-day treatment, the animals were sacrificed,and the ventral prostates (VP), seminal vesicles (SV), and levator ani(LA) were collected and weighed. The sexual organ weights were firststandardized as mg per 100 g of body weight, and the increase in organweight induced by the compounds of the present invention was compared tothe castrate control animals. The organ weight of the intact controlanimals is considered fully efficacious (100%). Super-anova (one factor)was used for statistical analysis.

[0361] The gain and loss of sexual organ weights reflect the changes ofcell number (DNA content) and cell mass (protein content), dependingupon the serum androgen concentration. See Y. Okuda et al., 145 J Urol.,188-191 (1991), the disclosure of which is herein incorporated byreference. Therefore, measurement of organ wet weights is sufficient toindicate the bioactivity of androgens and androgen antagonists. Inimmature castrated rats, replacement of exogenous androgens increasedthe weights of the ventral prostate (VP), the seminal vesicles (SV), andthe levator ani (LA) in a dose-dependent manner as shown in Table 4.TABLE 4 Androgen Induced Ventral Prostate, Seminal Vesicle, and LevatorAni Growth in castrated immature rats at oral dosing, once daily, for 3days, with fluoxymesterone (fluox) and Compound 105. Treatment VP VP effSV SV eff LA LA eff (mg/kg) (wet wt)¹ (% of intact)² (wet wt)¹ (%intact)² (wet wt)¹ (% intact)² Cx 24.2 ± 1.8  0.0 ± 8.1  7.7 ± 1.0  0.0± 20 27.7 ± 3.2   0.0 ± 163 intact 46.6 ± 3.4 100 ± 15 12.8 ± 1.3 100 ±25 29.5 ± 1.0 100 ± 60 105 (3) 26.9 ± 1.1 12 ± 5  8.5 ± 0.7  15 ± 1333.0 ± 2.4  306 ± 140 105 (10) 35.9 ± 2.7  52 ± 12  9.9 ± 0.4   42 ± 8.236.3 ± 1.3 498 ± 73 105 (30) 30.1 ± 2.1 26 ± 9 11.7 ± 1.4  78 ± 26 35.8± 1.2 469 ± 71 105 (100) 42.1 ± 1.6 80 ± 7 14.4 ± 1.0 131 ± 19 39.7 ±0.6 696 ± 36 Fluox (1) 49.3 ± 4.1 112 ± 18 24.3 ± 3.7 325 ± 73 44.6 ±4.0  977 ± 230 Fluox (3) 57.5 ± 2.4 148 ± 10 31.8 ± 4.2 472 ± 82 45.3 ±3.1 1020 ± 180 Fluox 82.3 ± 7.2 259 ± 32 46.7 ± 1.7 762 ± 34 49.8 ± 5.41280 ± 310 (100)

[0362] TABLE 5 Androgen Induced Ventral Prostate, Seminal Vesicle, andLevator Ani Growth in castrated immature rats at oral dosing, oncedaily, for 3 days, with fluoxymesterone (fluox) and Compound 123.Treatment VP VP eff SV SV eff (% LA LA eff (% (mg/kg) (wet wt)¹ (% ofintact)² (wet wt)¹ of intact)¹ (wet wt)¹ of intact)² Cx 26.6 ± 2.1  0.0± 12  9.4 ± 0.8  0.0 ± 11 30.0 ± 3.6  0.0 ± 163 intact 44.0 ± 5.1 100 ±29   17 ± 1.5 100 ± 19 32.1 ± 3.0 100 ± 137 123 (3) 28.8 ± 2.8  13 ± 1610.6 ± 0.9  15 ± 12 32.4 ± 3.6 109 ± 165 123 (10) 38.6 ± 0.6   69 ± 3.6 9.3 ± 0.3   −1 ± 4.2 34.4 ± 1.6 203 ± 75 123 (30) 37.9 ± 3.1 65 ± 1813.9 ± 0.8   57 ± 9.9 42.1 ± 2.7 554 ± 124 123 (100) 44.6 ± 5.3 101 ± 3019.6 ± 1.5 129 ± 19 48.5 ± 2.0 844 ± 91  Fluox (1) 31.8 ± 3.8  30 ± 2222.4 ± 3.2 165 ± 41 42.6 ± 2.6 574 ± 116 Fluox (3) 47.1 ± 3.4 118 ± 1929.0 ± 2.0 250 ± 26 51.8 ± 1.4 995 ± 65  Fluox 73.5 ± 3.5 269 ± 20 37.4± 1.1 356 ± 14 60.4 ± 1.1 1384 ± 51 (100)

[0363] In this immature castrated rat model, a known AR agonist(fluoxymesterone) was administered orally with 1.0, 3.0, and 100 mg/kg,increasing the androgen-mediated increases in the weights of VP, SV andLA in a dose-dependent manner as shown in Table 4. Compounds 105 and 123also exhibited AR agonist activity by promoting the androgen-mediatedmaintenance/increase in the weights of the VP, SV and LA as summarizedin Tables 4 and 5.

[0364] While in accordance with the patent statutes, description of thepreferred embodiments and processing conditions have been provided, thescope of the invention is not to be limited thereto or thereby. Variousmodifications and alterations of the present invention will be apparentto those skilled in the art without departing from the scope and spiritof the present invention, reference is made to the followingnon-limiting enumerated embodiments.

What is claimed is:
 1. A compound of the formula:

wherein: R¹ is selected from the group of hydrogen, F, Cl, Br, I, NO₂,OR⁹, NR¹⁰R¹¹, S(O)_(m)R⁹, C₁-C₈ alkyl, C₁-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, C₁-C₈ aryl, C₁-C₈ arylalkyl, C₁-C₈heteroaryl, C₂-C₈ alkynyl, and C₂-C₈ alkenyl and wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,alkynyl, and alkenyl groups are optionally substituted; R² is selectedfrom the group of hydrogen, F, Cl, Br, I, CF₃, CF₂Cl, CF₂H, CFH₂,CF₂OR⁹, CH₂OR⁹, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, and C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups are optionally substituted; R³ is selected from the groupof hydrogen, F, Cl, Br, I, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, or C₁-C₆ alkyl,C₁-C₆ heteroalkyl and C₁-C₆ haloalkyl and wherein the alkyl, heteroalkyland haloalkyl groups are optionally substituted; R⁴ and R⁵ are eachindependently selected from the group of hydrogen, OR⁹, S(O)_(m)R⁹,NR¹⁰R¹¹, C(Y)OR¹¹, C(Y)NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, and C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups are optionally substituted, or R⁴ and R⁵ taken togetherform a saturated or unsaturated three- to seven-membered ring that isoptionally substituted; R⁶ and R⁷ are each independently selected fromthe group of hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl,C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionallysubstituted, or R⁶ and R⁷ taken together form a saturated or unsaturatedthree- to seven-membered ring that is optionally substituted, or R⁶ andR⁵ taken together form a saturated or unsaturated three- toseven-membered ring that is optionally substituted; R⁸ is selected fromthe group of hydrogen, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl,F, Cl, Br, I, NO₂, OR⁹, NR¹⁰R¹¹ and S(O)_(m)R⁹ and wherein the alkyl,heteroalkyl and haloalkyl groups are optionally substituted; R⁹ isselected from the group of hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl,C₁-C₆ haloalkyl, aryl, heteroaryl, arylalkyl, C₂-C₄ alkynyl and C₂-C₈alkenyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, alkynyl, and alkenyl groups are optionally substituted; R¹⁰is selected from the group of hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl,C₁-C₆ haloalkyl, C(Y)R¹², C(Y)OR¹², aryl, heteroaryl, C₂-C₄ alkynyl,C₂-C₈ alkenyl, arylalkyl, SO₂R¹² and S(O)R¹² and wherein the alkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups are optionally substituted; R¹¹ is selected from thegroup of hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, arylalkyl, C₂-C₄ alkynyl and C₂-C₈ alkenyl and whereinthe alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl,and alkenyl groups are optionally substituted; R¹² is selected from thegroup of hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, arylalkyl, C₂-C₄ alkynyl and C₂-C₈ alkenyl and whereinthe alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl,and alkenyl groups are optionally substituted, R¹³ is selected from thegroup of hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl,C₁-C₈ haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, C₂-C₄alkynyl and C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkynyl, and alkenyl groups are optionally substituted; or R¹³ and R⁴taken together form a saturated or unsaturated three- to seven-memberedring that is optionally substituted; or any two of R⁴ through R⁷, andR¹³ taken together form a saturated or unsaturated three- toseven-membered ring that is optionally substituted; R¹⁴ and R¹⁵ are eachindependently selected from the group of hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, heteroaryl,arylalkyl, C₂-C₈ alkynyl and C₂-C₈ alkenyl and wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyland alkenyl are optionally substituted; R^(A) is selected from the groupof hydrogen, F, Br, Cl, I, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, OR¹⁶, NR¹⁶R¹⁷, SR¹⁶, CH₂R¹⁶, COR¹⁷, CO₂R¹⁷, CONR¹⁷R¹⁷,SOR¹⁷ and SO₂R¹⁷ and wherein the alkyl, haloalkyl and heteroalkyl groupsare optionally substituted; R¹⁶ is selected from the group of hydrogen,C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, COR¹⁷, CO₂R¹⁷,CONR¹⁷R¹⁷, C₂-C₈ alkynyl, C₂-C₈ alkenyl, aryl, and heteroaryl andwherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkynyl,and alkenyl groups are optionally substituted; R¹⁷ is selected from thegroup of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl and C₁-C₄ heteroalkyland wherein the alkyl, haloalkyl, and heteroalkyl groups are optionallysubstituted; m is 0, 1 or 2; n is 1 or 2; V is selected from the groupof O, S and CR¹⁴R¹⁵; W is selected from the group of 0, S, NH, NR¹³,NC(Y)R¹¹ and NSO₂R¹¹; X and Z each independently is selected from thegroup of O, S(O)_(m), NH, NR¹¹, NC(Y)R¹¹, NSO₂R¹² and NS(O)R¹²; and Y isO or S; and pharmaceutically acceptable salts thereof.
 2. A compoundaccording to claim 1, wherein Z is NR¹¹.
 3. A compound according toclaim 2, wherein R¹¹ is hydrogen.
 4. A compound according to claim 2,wherein R² is CF₃.
 5. A compound according to claim 1, wherein W isNR¹³.
 6. A compound according to claim 5, wherein R¹³ and one of R⁴ andR⁵ together form a five or six-membered ring.
 7. A compound according toclaim 5, wherein R¹³ is alkyl.
 8. A compound according to claim 7,wherein R¹³ is selected from the group of methyl, ethyl, propyl,isopropyl, cyclopropylmethyl, and t-butyl.
 9. A compound according toclaim 5, wherein R¹³ is haloalkyl.
 10. A compound according to claim 9,wherein R¹³ is trifluoroethyl.
 11. A compound according to claim 1,wherein each of R⁴, R⁵, R⁶ and R⁷ are independently hydrogen oroptionally substituted C₁-C₆ alkyl.
 12. A compound according to claim11, wherein one of R⁴, R⁵, R⁶ and R⁷ is optionally substituted C₁-C₆alkyl.
 13. A compound according to claim 11, wherein one of R⁴ and R⁵ isoptionally substituted C₁-C₆ alkyl.
 14. A compound according to claim13, wherein one of R⁴ and R⁵ is OR⁹.
 15. A compound according to any oneof claims 11 or 13, wherein one of R⁶ and R⁷ is optionally substitutedC₁-C₆ alkyl.
 16. A compound according to claim, 15, wherein one of R⁶and R⁷ is OR⁹.
 17. A compound according to claim 1, wherein R³ and R⁸are each hydrogen; X and Y are each independently O or S; W is NR¹³; andZ is NR¹¹.
 18. A compound according to claim 17, wherein X and Y areeach O.
 19. A compound according to claim 18, wherein R² is selectedfrom the group of hydrogen, halogen, CF₃, C₁-C₈ alkyl and C₁-C₈haloalkyl.
 20. A compound according to claim 19, wherein R² is CF₃
 21. Acompound according to claim 20, wherein R¹³ is selected from the groupof C₁-C₈ alkyl, C₃-C₈ cycloalkyl, and C₁-C₈ haloalkyl.
 22. A compoundaccording to claim 21, wherein R¹³ is C₁-C₈ alkyl or C₁-C₈ haloalkyl.23. A compound according to claim 21, wherein R¹¹ is selected from thegroup of hydrogen, optionally substituted C₁-C₆ alkyl and C₁-C₆heteroalkyl.
 24. A compound according to claim 23, wherein R¹¹ ishydrogen or optionally substituted C₁-C₆ alkyl.
 25. A compound accordingto claim 24, wherein R¹¹ is hydrogen.
 26. A compound according to claim23, wherein R⁶ and R⁷ are each independently selected from the group ofhydrogen, C₁-C₈ alkyl, and C₁-C₈ haloalkyl.
 27. A compound according toclaim 26, wherein R⁶ and R⁷ are each independently hydrogen or C₁-C₈alkyl.
 28. A compound according to claim 27, wherein R⁶ and R⁷ are eachhydrogen.
 29. A compound according to claim 26, wherein R⁴ and R⁵ areeach independently selected from the group of hydrogen, C₁-C₈ alkyl, andOR⁹.
 30. A compound according to claim 29, wherein R⁴ and R⁵ are eachindependently hydrogen or C₁-C₈ alkyl.
 31. A compound according to claim30, wherein R⁴ and R⁵ are each hydrogen.
 32. A compound according toclaim 1, wherein: R¹ is selected from the group of hydrogen, F, Cl, Br,I, C₁-C₆ alkyl and C₁-C₆ haloalkyl; R² is selected from the group ofhydrogen, halogen, CF₃, C₁-C₈ alkyl, and C₁-C₈ haloalkyl; R³ is selectedfrom the group of hydrogen, C₁-C₈ alkyl, and C₁-C₈ haloalkyl; R⁴ and R⁵are each independently selected from the group of hydrogen, C₁-C₈ alkyl,C₁-C₄ haloalkyl, C₁-C₄ heteroalkyl and OR⁹; R⁶ and R⁷ are eachindependently hydrogen or C₁-C₈ alkyl; R⁸ is selected from the group ofhydrogen, F, Cl, Br, I, C₁-C₄ alkyl and C₁-C₄ haloalkyl; R^(A) isselected from the group of hydrogen, F, Cl, Br, I, C₁-C₆ alkyl and C₁-C₆haloalkyl; m is 1 or 2; W is selected from the group of O, NH, NR¹³,NC(Y)R¹¹, and NSO₂R¹¹; X and Z are each independently selected from thegroup of O, S and NR¹¹; and Y is O.
 33. A compound according to claim32, wherein: R¹, R³ and R⁸ are each hydrogen; R² is CF₃ or haloalkyl;R⁵, R⁶, and R⁷ each are independently hydrogen or C₁-C₈ alkyl; m is 1; Wis NH or NR¹³; X and Z are each independently O or NR¹¹; and Y is O. 34.A compound according to claim 33, wherein: R² is CF₃; R⁴ is selectedfrom the group of hydrogen, C₁-C₄ alkyl, and C₁-C₂ haloalkyl; R⁵, R⁶,and R⁷ are each independently hydrogen; W is NR¹³; X is O; and Z isNR¹¹.
 35. A method for the preparation of compounds of the formula:

wherein: R³ is selected from the group of hydrogen, F, Cl, Br, I, OR⁹,S(O)_(m)R⁹, NR¹⁰R¹¹, or C₁-C₆ alkyl, C₁-C₆ heteroalkyl and C₁-C₆haloalkyl and wherein the alkyl, heteroalkyl and haloalkyl groups areoptionally substituted; R⁴ and R⁵ are each independently selected fromthe group of hydrogen, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C(Y)OR¹¹, C(Y)NR¹⁰R¹¹,C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl,arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈ alkenyl and wherein thealkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,alkynyl, and alkenyl are optionally substituted, or R⁴ and R⁵ takentogether can form a three- to seven-membered ring that is optionallysubstituted; R⁶ and R⁷ are each independently selected from the group ofhydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈ alkenyland wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted,or R⁶ and R⁷ taken together can form a three- to seven-membered ringthat is optionally substituted; or R⁶ and R⁵ taken together form athree- to seven-membered ring that optionally substituted; or any two ofR⁴ through R⁷ taken together form a three- to seven-membered ring thatis optionally substituted; R⁸ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, F, Cl, Br, I, NO₂, OR⁹,NR¹⁰R¹¹ and S(O)_(m)R⁹ and wherein the alkyl, heteroalkyl, and haloalkylgroups are optionally substituted; R⁹ is selected from the group ofhydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl,heteroaryl, C₃-C₆ alkenyl and arylalkyl and wherein the alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groupsare optionally substituted; R¹⁰ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl, arylalkyl, SO₂R¹² and S(O)R¹² and wherein the alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groupsare optionally substituted; R¹¹ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl,aryl, heteroaryl, alkenyl and arylalkyl groups are optionallysubstituted; R¹² is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆haloalkyl, aryl, heteroaryl, C₃-C₆ alkenyl or arylalkyl and wherein thealkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkylgroups are optionally substituted; R¹³ is selected from the group ofhydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈haloalkyl, aryl, heteroaryl, C₃-C₈ alkenyl, arylalkyl andheteroarylalkyl and wherein the alkyl, cycloalkyl, heteroalkyl,haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups are optionallysubstituted; m is 0, 1, or 2; that comprises the steps of: (a) treatingeither a single enantiomer, diastereomers, or the racemate of aβ-aminoalcohol of the formula:

 with a 3,4-dihalonitrobenzene of the formula:

 where X is fluorine or chlorine, to afford arylamino alcohol 36

(b) treating arylamino alcohol 36 with aldehyde R^(x)(CO)H or thecorresponding hydrate or hemiacetal R^(x) HC(OH)(OR), where R is H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₁-C₁₀ haloalkyl, and R^(x) CH₂ isequivalent to R¹³, to form oxazolidine 37

(c) reducing oxazolidine 37 to form amino alcohol 38

(d) treating amino alcohol 38 with a base to form the3,4-dihydro-7-nitro-2H-1,4-benzoxazine intermediate 39

 as either a single enantiomer, diastereomers or the racemate.
 36. Amethod according to claim 35, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹³each independently are selected from the group of hydrogen, C₁-C₆ alkyland C₁-C₆ haloalkyl.
 37. A method according to claim 36, wherein R³, R⁶,R⁷, and R⁸ each are hydrogen.
 38. A method according to claim 37,wherein one of R⁴ and R⁵ is hydrogen and the other one of R⁴ and R⁵ isC₁-C₆ alkyl or C₁-C₆ haloalkyl.
 39. A method according to claim 38,wherein R¹³ is C₁-C₆ alkyl or C₁-C₆ haloalkyl.
 40. A method for thepreparation of compounds of the formula:

wherein: R³ is selected from the group of hydrogen, F, Cl, Br, I, OR⁹,S(O)_(m)R⁹, NR¹⁰R¹¹, or C₁-C₆ alkyl, C₁-C₆ heteroalkyl and C₁-C₆haloalkyl and wherein the alkyl, heteroalkyl, and haloalkyl groups areoptionally substituted; R⁴ and R⁵ are each independently selected fromthe group of hydrogen, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C(Y)OR¹¹, C(Y)NR¹⁰R¹¹,C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl,arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈ alkenyl and wherein thealkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,alkynyl, and alkenyl groups are optionally substituted, or R⁴ and R⁵taken together can form a three- to seven-membered ring that isoptionally substituted; R⁶ and R⁷ are each independently selected fromthe group of hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl,C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionallysubstituted, or R⁶ and R⁷ taken together form a three- to seven-memberedring that is optionally substituted; or any two of R⁴ through R⁷ takentogether can form a three- to seven-membered ring that is optionallysubstituted; or R⁶ and R⁵ taken together form a three- to seven-memberedring that is optionally substituted; R⁸ is selected from the group ofhydrogen, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, F, Cl, Br, I,NO₂, OR⁹, NR¹⁰R¹¹ and S(O)_(m)R⁹ and wherein the alkyl, heteroalkyl, andhaloalkyl groups are optionally substituted; R⁹ is selected from thegroup of hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,aryl, heteroaryl, C₃-C₆ alkenyl and arylalkyl and wherein the alkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groupsare optionally substituted; R¹⁰ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl, arylalkyl, SO₂R¹² and S(O)R¹² and wherein the alkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groupsare optionally substituted; R¹¹ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, and alkenyl groups are optionallysubstituted; R¹² is selected from the group of hydrogen, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆ allyl andarylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;R¹³ is selected from the group of hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, heteroaryl, C₃-C₈alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, andalkenyl groups are optionally substituted; m is 0, 1, or 2; thatcomprises the steps of: (a) treating either a single enantiomer,diastereomers, or the racemate of a β-aminoalcohol of the formula:

 with a 3,4-dihalonitrobenzene of the formula:

 where X is fluorine or chlorine, to afford arylamino alcohol 36

(b) treating arylamino alcohol 36 with aldehyde R^(x)(CO)H or thecorresponding hydrate or hemiacetal R^(x) HC(OH)(OR), where R is H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₁-C₁₀ haloalkyl, and R^(x) CH₂ isequivalent to R¹³, to form oxazolidine 37

(c) reducing oxazolidine 37 to form amino alcohol 38

(d) treating amino alcohol 38 with a base to form the3,4-dihydro-7-nitro-2H-1,4-benzoxazine compound 39

(e) treating nitro benzoxazine compound 39 with a reducing agent to formamino benzoxazine compound 40:


41. A method according to claim 40, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ andR¹³ are each independently selected from the group of hydrogen, C₁-C₆alkyl or C₁-C₆ haloalkyl.
 42. A method according to claim 41, whereinR³, R⁶, R⁷, and R⁸ each are hydrogen.
 43. A method according to claim42, wherein one of R⁴ and R⁵ is hydrogen and the other one of R⁴ and R⁵is C₁-C₆ alkyl or C₁-C₆ haloalkyl.
 44. A method according to claim 43,wherein R¹³ is C₁-C₆ alkyl or C₁-C₆ haloalkyl.
 45. A compound accordingto claim 1, wherein said compound is selected from the group of:1,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1-Ethyl-1,2,3,6-tetrahydro-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,8-Fluoro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,8-Chloro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,9-(Difluoromethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-Tetrahydro-6-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,7-Chloro-2,3-dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline,1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-thione,1,2,3,6-Tetrahydro-1-propyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-Tetrahydro-1-isobutyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-Tetrahydro-1-isobutyl-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(−)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-1,3-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-3-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-3-Ethyl-1,2,3,6-tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1-Cyclopropylmethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-Tetrahydro-1-(pyridylmethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(−)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-trans-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-cis-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-trans-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-cis-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-2-(acetoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(+)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-2-(Ethoxymethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-2-(propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2-Dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3,2-g]quinolin-2,7-dione,(±)-1,2,3,6-Tetrahydro-2-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2-Dihydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3,2-g]-quinolin-2,7-dione1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-2-thioxo-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1-Cyclopropylmethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-2-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1-Cyclopropylmethyl-2-ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,1,2,3,6-Tetrahydro-1-isopropyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2-Diethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(+)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(−)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1-Ethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(2R)-(−)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(2R)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(2R)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(2R)-1,2,3,6-Tetrahydro-2-isopropyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one,(±)-1,2,3,4,4a,5-Hexahydro-11-(trifluoromethyl)-pyrido[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-7-one,(R)-2,3,3a,4-Tetrahydro-10-(trifluoromethyl)-pyrrolo[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one,1,3,4,6-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)-pyrazino[3,2-g]quinolin-2,7-dione,1,2,3,4-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)-pyrazino[3,2-g]quinolin-7(6H)one,9-(Trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one,1-Methyl-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one,1-(2,2,2-Trifluoroethyl)-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one.46. A pharmaceutical composition comprising in a pharmaceuticallyacceptable vehicle suitable for enteral, parenteral, or topicaladministration, one or more compounds according to any one of claims 1,20, 23, 26 and
 29. 47. A compound according to any one of claims 1, 20,23, 26 and 29 for administration to a mammalian subject to modulate aprocess mediated by one or more steroid receptors from the groupconsisting of progesterone receptors, androgen receptors, estrogenreceptors, glucorticoid receptors, and mineralocorticoid receptors. 48.A compound according to any one of claims 1, 20, 23, 26 and 29 for usein modulation of male and female hormone responsive diseases.
 49. Amethod for the preparation of compounds of the formula:

wherein: R¹ is selected from the group of hydrogen, F, Cl, Br, I, NO₂,OR⁹, NR¹⁰R¹¹, S(O)_(m)R⁹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, and C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups are optionally substituted; R² is selected from the groupof hydrogen, F, Cl, Br, I, CF₃, CF₂H, CFH₂, CF₂OR⁹, CH₂OR⁹, OR⁹,S(O)_(m)R⁹, NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl,C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionallysubstituted; R³ is selected from the group of hydrogen, F, Cl, Br, I,OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, or C₁-C₆ alkyl, C₁-C₆ heteroalkyl and C₁-C₆haloalkyl and wherein the alkyl, heteroalkyl, and haloalkyl groups areoptionally substituted; R⁴ and R⁵ are each independently is selectedfrom the group of hydrogen, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C(Y)OR¹¹,C(Y)NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl and C₂-C₈ alkenyland wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionallysubstituted, or R⁴ and R⁵ taken together a three- to seven-membered ringthat is optionally substituted; R⁶ and R⁷ are each independently isselected from the group of hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, and C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups are optionally substituted; or R⁶ and R⁷ taken togetherform a three- to seven-membered ring that is optionally substituted; orany two of R⁴ through R⁷ taken together can form a three- toseven-membered ring that is optionally substituted; or R⁶ and R⁵ takentogether form a three- to seven-membered ring that is optionallysubstituted; R⁸ is selected from the group of hydrogen, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, F, Cl, Br, I, NO₂, OR⁹, NR¹⁰R¹¹ andS(O)_(m)R⁹ and wherein the alkyl, heteroalkyl, and haloalkyl groups areoptionally substituted; R⁹ is selected from the group of hydrogen, C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, and alkenyl groups are optionallysubstituted; R¹⁰ is selected from the group of hydrogen, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆ alkenyl,arylalkyl, SO₂R¹² and S(O)R¹² and wherein the alkyl, heteroalkyl,haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups areoptionally substituted; R¹¹ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, and alkenyl groups are optionallysubstituted; R¹² is selected from the group of hydrogen, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆ alkenyl andarylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;R¹³ is selected from the group of hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, heteroaryl, C₃-C₈alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, andalkenyl groups are optionally substituted; R^(A) is hydrogen, F, Br, Cl,I, CN, a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, OR¹⁶, NR¹⁶R¹⁷,SR¹⁶, CH₂R¹⁶, COR¹⁷, CO₂R¹⁷, CONR¹⁷R¹⁷, SOR¹⁷ or SO₂R¹⁷ and wherein thealkyl, heteroalkyl, and haloalkyl groups are optionally substituted; R¹⁶is selected from the group of hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl.,C₁-C₈ heteroalkyl, COR¹⁷, CO₂R¹⁷ and CONR¹⁷R¹⁷ and wherein the alkyl,heteroalkyl, and haloalkyl groups are optionally substituted; R¹⁷ isselected from the group of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl andC₁-C₄ heteroalkyl and wherein the alkyl, heteroalkyl, and haloalkylgroups are optionally substituted; m is 0, 1, or 2; Y is O or S; Z isselected from the group of O, S(O)_(m), NH, NR¹¹, NC(Y)R¹¹, NSO₂R¹² andNS(O)R¹²; that comprises the steps of: (a) treating either a singleenantiomer, diastereomers, or the racemate of a β-aminoalcohol of theformula:

 with a 3,4-dihalonitrobenzene of the formula

 where X is fluorine or chlorine, to afford arylamino alcohol 36

(b) treating arylamino alcohol 36 with aldehyde R^(x)(CO)H or thecorresponding hydrate or hemiacetal R^(x) HC(OH)(OR), where R is H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₁-C₁₀ haloalkyl, and R^(x) CH₂ isequivalent to R¹³, to form oxazolidine 37

(c) reducing oxazolidine 37 to form amino alcohol 38

 and (d) treating amino alcohol 38 with a base to form the3,4-dihydro-7-nitro-2H-1,4-benzoxazine intermediate 39

(e) treating nitro benzoxazine compound 39 with a reducing agent to formamino benzoxazine compound 40

 as either a single enantiomer, diastereomers, or the racemate; and (f)treating amino benzoxazine compound 40 with a β-ketoester or itscorresponding hydrate at elevated temperature to form acetanilidecompound; and (g) treating said acetanilide compound with an acid toyield quinoline compound 41:


50. A method according to claim 49, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ andR¹³ are each independently selected from the group of hydrogen, C₁-C₆alkyl or C₁-C₆ haloalkyl.
 51. A method according to claim 49, whereinR³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each hydrogen.
 52. A method for thepreparation of N-(2-haloethyl) arylamino alcohols comprising: (a)treating either a single enantiomer, diastereomers, or the racemate ofan arylamino alcohol of the formula

 with aldehyde CH_(n)X_(3-n)COH or the hydrate or hemiacetalCH_(n)X_(3-n)CH(OH)OR, where X is a halogen, n is 0, 1 or 2, and R isselected from the group of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₁-C₁₀haloalkyl, in the presence of an acid catalyst to form an oxazolidine ofthe formula:

 and (b) treating said oxazolidine with a reducing agent, preferablytriethylsilane or sodium cyanoborohydride, in the presence of a Lewisacid or a Bronsted acid as a catalyst to form a product of the formula:

 wherein R⁴⁻⁷ are each independently selected from the group of hydrogenC₁-C₈ alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl,heteroaryl, alkynyl, and alkenyl, and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl are optionally substituted; and Ar is aryl or heteroaryl,optionally substituted at one or more positions; as either a singleenantiomer, diastereomers, or the racemate.
 53. A method for thepreparation of compounds of the formula

wherein: R¹ is selected from the group of hydrogen, F, Cl, Br, I, NO₂,OR⁹, NR¹⁰R¹¹, S(O)_(m)R⁹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, C₂-C₈ alkenyl and whereinthe alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, alkynyl, and alkenyl groups are optionally; R² is selectedfrom the group of hydrogen, F, Cl, Br, I, CF₃, CF₂H, CFH₂, CF₂OR⁹,CH₂OR⁹, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈heteroalkyl, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈alkynyl, and C₂-C₈ alkenyl and wherein the alkyl, cycloalkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, andalkenyl groups are optionally substituted; R³ is selected from the groupof hydrogen, F, Cl, Br, I, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C₁-C₆ alkyl, C₁-C₆heteroalkyl and C₁-C₆ haloalkyl; R⁴ and R⁵ are each independentlyselected from the group of hydrogen, OR⁹, S(O)_(m)R⁹, NR¹⁰R¹¹, C(Y)OR¹¹,C(Y)NR¹⁰R¹¹, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈ alkenyland wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted,or R⁴ and R⁵ taken together form a three- to seven-membered ring that isoptionally substituted; R⁶ and R⁷ are each independently selected fromthe group of hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl,C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, C₂-C₈ alkynyl, and C₂-C₈alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted;or R⁶ and R⁷ taken together form a three- to seven-membered ring that isoptionally substituted; or any two of R⁴ through R⁷ taken together canform a three- to seven-membered ring that is optionally substituted; R⁶and R⁵ taken together form a three- to seven-membered ring that isoptionally substituted; R⁸ is selected from the group of hydrogen, C₁-C₄alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, F, Cl, Br, I, NO₂, OR⁹,NR¹⁰R¹¹ and S(O)_(m)R⁹ and wherein the alkyl, heteroalkyl, and haloalkylgroups are optionally substituted; R⁹ is selected from the group ofhydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl,heteroaryl, C₃-C₆ alkenyl and arylalkyl and wherein the alkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groupsare optionally substituted; R¹⁰ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl, arylalkyl, SO₂R¹² and S(O)R¹² and wherein the alkyl,heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groupsare optionally substituted; R¹¹ is selected from the group of hydrogen,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, and alkenyl groups are optionallysubstituted; R¹² is selected from the group of hydrogen, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₃-C₆ alkenyl andarylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl,arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;R¹³ is selected from the group of hydrogen, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, aryl, heteroaryl, C₃-C₈alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,arylalkyl and alkenyl groups are optionally substituted; R^(A) isselected from the group of hydrogen, F, Br, Cl, I, CN, a C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, OR¹⁶, NR¹⁶R¹⁷, SR¹⁶, CH₂R¹⁶, COR¹⁷,CO₂R¹⁷, CONR¹⁷R¹⁷, SOR¹⁷ and SO₂R¹⁷ and wherein the alkyl, haloalkyl andheteroalkyl are optionally substituted; R¹⁶ is selected from the groupof hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, COR¹⁷,CO₂R¹⁷ and CONR¹⁷R¹⁷ and wherein the alkyl, heteroalkyl, and haloalkylgroups are optionally substituted; R¹⁷ is selected from the group ofhydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl and C₁-C₄ heteroalkyl and whereinthe alkyl, haloalkyl and heteroalkyl groups are optionally substituted;m is 0, 1, or 2; Y is O or S; Z is selected from the group of O,S(O)_(m), NH, NR¹¹, NC(Y)R¹¹, NSO₂R¹² or NS(O)R¹²; that comprises thesteps of: (a) treating either a single enantiomer, diastereomers, or theracemate of a secondary aminoalcohol of the formula

 with a 3,4-dihalonitrobenzene of the formula

 where X is fluorine or chlorine, to afford tertiary aminoalcohol 42

(b) treating tertiary aminoalcohol 42 with a base to form the3,4-dihydro-7-nitro-2H-1,4-benzoxazine intermediate 39

 as either a single enantiomer, diastereomers, or the racemate.